5-HT7 receptor antagonists

ABSTRACT

The present invention relates to compounds having pharmacological activity toward the 5-HT 7  receptor. Pharmaceutical compositions and methods for their use in the treatment of CNS disorders are described.

This application is a divisional of Ser. No. 09/344,916, filed Jun. 25,1999, now U.S. Pat. No. 6,239,143, which claims priority fromProvisional application Ser. No. 60/091,254, filed Jun. 30, 1998.

FIELD OF THE INVENTION

The present invention relates to compounds having pharmacologicalactivity toward the 5-HT₇ receptor. Pharmaceutical compositions andmethods for their use in the treatment of CNS disorders are described.

BACKGROUND OF THE INVENTION

The 5-HT₇ receptor is the most recent addition to the burgeoning familyof 5-HT receptors. 5-HT₇ receptors have been cloned from rat, mouse,guinea pig, and human cDNA and exhibit a high degree of interspecieshomology, (approximately 95%) but a low sequence homology with other5-HT receptors (<40%). The pharmacological profile of this receptor isunique yet consistent across species. Thus, high 5-HT₇ receptor affinityis observed from 5-CT, 5-HT, 5-MeOT, and methiothepin, moderate affinityfor 8-OHDPAT, clozapine, and ritanserin, and low affinity for pindolol,sumatriptan, and buspirone. Recent data have demonstrated the existenceof four 5-HT₇ splice variants in humans and three in rat (Heidmann, etal., J. Neurochem., 1997, 68, 1372-1381). Preliminary pharmacologicalcomparison of the long (5-HT_(7a)) and short (5-HT_(7b)) forms of thereceptor have revealed no substantial differences in receptor bindingaffinity (Jasper et al., J. Pharmocol., 1997, 120, 298). 5-HT₇ receptorsare positively coupled to adenylate cyclase when expressed in celllines, native guinea pig hippocampus, and cultured vascular smoothmuscle cells.

The greatest abundance of 5-HT₇ mRNA is found in the brain where it isdiscretely located within thalamus, hypothalamus, and various limbic andcortical regions. Autoradiographic techniques confirm that thedistribution of 5-HT₇ receptor binding sites in rat and guinea pig brainmatches, to a large extent, the mRNA distribution (To, et al., J.Pharmocol., 1995, 115, 107-116).

Preliminary data support that the 5-HT₇ receptor may be involved in thepathophysiology of sleep disorders, depression, (Schwartz, et al., Adv.Int. Med. 1993, 38, 81-106) and schizophrenia (Roth, et al., J.Pharmacol. Exp. Ther., 1994, 268, 1403-1410). The 5-HT₇ receptorstimulation has caused relaxation of the blood vessels in monkey (Leung,et al. Br. J. Pharmocol., 1996, 117, 926-930), dog (Cushing, et al. J.Pharmocol. Exp. Ther., 1996, 277, 1560-1566) and rabbit (Martin, et al.,Br. J. Pharmocol., 1995, 114, 383). Therefore, the therapeutic utilityof 5-HT₇ receptor ligands requires the discovery of selectivetherapeutic agents. The present invention discloses novel 5-HT₇ receptorantagonists.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelinhibitors of the 5-HT₇ receptor or pharmaceutically acceptable salts orprodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating central nervous system disorders comprising administering to ahost in need of such treatment a therapeutically effective amount of atleast one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I):

or pharmaceutically acceptable salt forms thereof, wherein R¹, X, Y, nand A are defined below, are effective 5-HT₇ inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novelcompound of formula (I):

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein:

R¹ is selected from a C₆₋₁₀ carbocyclic aromatic residue substitutedwith 1-3 R^(1a), and a 5-10 membered aromatic heterocyclic systemcontaining from 1-4 heteroatoms selected from N, O, and S substitutedwith 0-2 R^(1a);

R^(1a) is independently selected at each occurrence from halo, —NO₂,—CN, —CF₃ and —CF₂CF₃;

X is selected from —S(O)_(p)—, —C(O)—, —O—, —CH(OH)—, —CH(OC(O)CH₃)—,—NR^(4a)—, —S(O)₂NR⁴— and a five membered saturated, partially saturatedor unsaturated ring containing 0-2 heteroatoms selected from the groupconsisting of O and N;

with the proviso that when X is a five membered saturated, partiallysaturated or unsaturated ring containing 0-2 heteroatoms selected from Oand N, R¹ may be an unsubstituted C₆₋₁₀ carbocyclic aromatic residue;

R⁴ is selected from hydrogen and C₁₋₆ alkyl;

R^(4a) is taken together with R¹ to form a 5 or 6-membered fusedheterocyclic ring containing 1-2 heteroatoms selected from O or N, andsubstituted with 1 or 2 carbonyl groups;

Y is C₁₋₃ alkylene;

A is selected from a 5 or 6 membered saturated, partially saturated orunsaturated ring which contains from 0-1 heteroatoms selected from N, Oand S substituted with 0-3 R⁵, napthyl substituted with 0-3 R⁵, andnapthyl fused with ring B substituted with 0-3 R⁵;

R⁵ is selected from C₁₋₅ alkyl, halo and —OCH₃;

n is selected from 1, 2, and 3; and

p is selected from 0, 1, and 2.

[2] In a preferred embodiment, the present invention provides novelcompounds, wherein:

R¹ is phenyl substituted with 1-3 R^(1a);

R^(1a) is selected independently at each occurrence from halo, —CN, —CF₃and —CF₂CF₃;

X is selected from —S(O)₂—, —S—, —NR^(4a)—, —C(O)—, isoxazolyl andisoxazolinyl;

R^(4a) is taken together when R¹ is phenyl to form a 5 membered fusedcyclic urea;

Y is propylene;

A is selected from phenyl substituted with 0-3 R⁵, napthyl substitutedwith 0-3 R⁵ and napthyl fused with ring B substituted with 0-3 R⁵;

R⁵ is selected independently at each occurrence from C₁₋₅ alkyl, haloand —OCH₃; and

n is selected from 1 and 2.

[3] In a more preferred embodiment, the present invention provides novelcompounds, wherein:

R¹ is phenyl substituted with 1-3 R^(1a);

R^(1a) is selected independently at each occurrence from para-halo andmeta-fluoro;

X is selected from —S(O)₂—, —S— and —C(O)—;

Y is propylene;

A is phenyl substituted with 0-2 R⁵;

R⁵ is selected independently at each occurrence from C₁₋₅ alkyl, haloand —OCH₃; and

n is selected from 1 and 2.

[4] In a further more preferred embodiment, the present inventionprovides novel compounds, wherein:

R¹ is phenyl substituted with 1-3 R^(1a);

R^(1a) is meta-fluoro;

X is selected from —S(O)₂—, —S— and —C(O)—;

Y is propylene;

A is phenyl substituted with 0-2 R⁵;

R⁵ is selected independently at each occurrence from C₁₋₅ alkyl, haloand —OCH₃; and

n is selected from 1 and 2.

[5] In an even further more preferred embodiment, the present inventionprovides a compound selected from the group:

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))isoindole,

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-hydroxybutyl)) isoindole,

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-acetoxybutyl)) isoindole,

2-((4-(4-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) benz[f]isoindole,

2-((4-(4-Pyridyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,

2-((4-(3-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))-1H-benz[de]isoquinoline,

2-((4-Oxo-4-(2-thienyl)butyl))-1,2,3,4-tetrahydroisoquinoline,

6,7-Dimethoxy-2-((4-(4-fluorophenyl)oxobutyl))-1,2,3,4-tetrahydroisoquinoline,

2-((3-(1,3-Dihydro-2H-benzimidazol-2-one)-1-ylpropyl))-1,2,3,4-tetrahydroisoquinoline,

2-(3-Phenylisoxazol-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline,

(+/−)-2-((3-(4-Fluorophenyl)-2-isoxazolin-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline,

1,3-Dihydro-2-((3-(4-fluorophenoxy)propyl))isoindole,

2-((3-(4-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline,

1,3-Dihydro-2-((3-(4-fluorophenylthio)propyl))isoindole,

1,3-Dihydro-2-((3-(4-fluorophenylsulfonyl)propyl)) isoindole,

2-((3-(4-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline

2-((3-(3-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline

2-((3-(3-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline

1,3-Dihydro-2-((4-(4-pyridyl)-4-oxobutyl))isoindole,

1,3-Dihydro-2-((4-(3-pyridyl)-4-oxobutyl))isoindole,

1,3-Dihydro-2-((4-(4-nitrophenyl)-4-oxobutyl))isoindole,

1,3-Dihydro-2-((4-(3-nitrophenyl)-4-oxobutyl))isoindole,

1,3-Dihydro-2-((4-(2-thienyl)-4-oxobutyl))isoindole,

1,3-Dihydro-2-((4-(3-thienyl)-4-oxobutyl))isoindole,

2-((4-(3-Pyridyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,

2-( (4-(4-Nitrophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,

2-((4-(3-Nitrophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,

2-((4-(3-Thienyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,

2-((3-(4-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,

2-((3-(4-Pyridylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,

2-((3-(4-Nitrophenylsulfonyl)propyl) )-1,2,3,4-tetrahydroisoquinoline,

2-((3-(3-Nitrophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,

2-((3-(2-Thienylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,

2-((3-(3-Thienylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,

1,3-Dihydro-2-((1-(3-thienylsulfonyl)propyl))isoindole,

1,3-Dihydro-2-((1-(2-thienylsulfonyl)propyl))isoindole,

1,3-Dihydro-2-((1-(4-fluorophenylsulfonyl)propyl)) isoindole,

1,3-Dihydro-2-((1-(3-fluorophenylsulfonyl)propyl)) isoindole,

1,3-Dihydro-2-((1-(4-nitrophenylsulfonyl)propyl)) isoindole,

1,3-Dihydro-2-((1-(3-nitrophenylsulfonyl)propyl)) isoindole,

1,3-Dihydro-2-((1-(4-pyridylsulfonyl)propyl))isoindole, and

1,3-Dihydro-2-((1-(3-pyridylsulfonyl)propyl))isoindole.

[6] In a second embodiment, the present invention provides a novelcompound of formula (II):

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein:

R¹ is selected from a C₆₋₁₀ carbocyclic aromatic residue substitutedwith 1-3 R^(1a), and a 5-10 membered aromatic heterocyclic systemcontaining from 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(1a);

R^(1a) is independently selected at each occurrence from(CH₂)_(r)OR^(1d), halo, C₁₋₄ alkyl, (CH₂)_(r)—C₃₋₆ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, —CN, —NO₂, —OCF₃, (CH₂)_(r)NR^(1b)R^(1c),(CH₂)_(r)SO₂R^(1d), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)OR^(1d),(CH₂)_(r)OC(O)R^(1d), (CH₂)_(r)C(O)R^(1d), (CH₂)_(r)NR^(1b)C(O)R^(1c),(CH₂)_(r)C(O)NR^(1b)R^(1c), (CH₂)_(r)SR^(1d),(CH₂)_(r)CH(═NR^(1b))NR^(1b)R^(1c), (CH₂)_(r)SO₂NR^(1b)R^(1c),(CH₂)_(r)SO₂NR^(1b)R^(1c), (CH₂)_(r)(CF₂)_(r)CF₃ and (CH₂)_(r)-phenylsubstituted with 0-3 R^(1e);

R^(1b) and R^(1c) are independently selected at each occurrence fromhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and(CH₂)_(r)-phenyl substituted with 0-3 R^(1e);

R^(1d) is independently selected at each occurrence from C₁₋₆ alkyl and(CH₂)_(r)-phenyl substituted with 0-2 R^(1e);

R^(1e) is independently selected at each occurrence from H,—(CH₂)_(r)OR^(1e), halo, C₁₋₄ alkyl, CN, NO₂, and —CF₃;

R^(1f) is selected from hydrogen and C₁₋₅ alkyl;

R^(1g) is C₁₋₅ alkyl;

X is selected from —CR⁶R⁷—, —CR²R³—, —C(O)—, —O—, —S(O)₂—, —S(O)₂NR⁴—and NR^(4a);

R⁴ is selected independently at each occurrence from hydrogen, C₁₋₆alkyl, (CH₂)_(r)—C₃₋₇ cycloalkyl, (CH₂)_(r)-aryl, and(CH₂)_(r)-heteroaryl;

R^(4a) is taken together with R¹ to form a 5 or 6-membered fusedheterocyclic ring containing 1-2 heteroatoms selected from O and N,substituted with 1 or 2 carbonyl groups;

R⁶ is selected independently at each occurrence from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(r)—C₃₋₆ cycloalkyl,(CH₂)_(r)-phenyl, —OH, —OC(O)R^(6a), C(O)R^(6a) and C(O)OR^(6a);

R^(6a) is selected independently from C₁₋₆ alkyl, phenyl and benzyl;

R⁷ is selected from hydrogen and C₁₋₅ alkyl;

A is selected from a 5 or 6 membered saturated, partially saturated orunsaturated ring which contains from 0-1 heteroatoms selected from N, Oand S substituted with 0-3 R⁵, napthyl substituted with 0-3 R⁵, andnapthyl fused with ring B substituted with 0-3 R⁵;

R⁵ is selected independently at each occurrence from (CH₂)_(r)OR^(5d),halo, C₁₋₄ alkyl, (CH₂)_(r)—C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,—CN, —NO₂, —OCF₃, (CH₂)_(r)NR^(5b)R^(5c), (CH₂)_(r)SO₂R^(5d),(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)OR^(5d), (CH₂)_(r)OC(O)R^(5d),(CH₂)_(r)C(O)R^(5b), (CH₂)_(r)NR^(5b)C(O)R^(5c),(CH₂)_(r)C(O)NR^(5b)R^(5c), (CH₂)_(r)SR^(5d),(CH₂)_(r)CH(═NR^(5b))NR^(5b)R^(5c), (CH₂)_(r)SO₂NR^(5b)R^(5c),(CH₂)_(r)SO₂NR^(5b)R^(5c), (CH₂)_(r)(CF₂)_(r)CF₃ and (CH₂)_(r)-phenylsubstituted with 0-3 R^(5e);

R^(5b) and R^(5c) are independently selected at each occurrence fromhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(r)-phenyl;

R^(5d) is independently selected at each occurrence from C₁₋₆ alkyl,phenyl substituted with 0-2 R^(5e), and benzyl substituted with 0-2R^(5e);

R^(5e) is independently selected at each occurrence from hydrogen,—(CH₂)_(r)OR^(5f), halo, C₁₋₄ alkyl, CN, NO₂, and —CF₃;

R^(5f) is selected from hydrogen and C₁₋₅ alkyl;

R^(5g) is C₁₋₅ alkyl;

n is selected from 1, 2, and 3;

r is selected from 0, 1, and 2.

[7] In a preferred embodiment, the present invention provides novelcompounds, wherein:

R¹ is phenyl substituted with 1-3 R^(1a);

R^(1a) is selected from halo, —CN, —CF₃ and —CF₂CF₃;

A is selected from phenyl substituted with 0-3 R⁵, napthyl substitutedwith 0-3 R⁵ and napthyl fused to ring B substituted with 0-3 R⁵;

X is selected from —C(O)— and —S(O)₂—;

R⁵ is independently selected at each occurrence from C₁₋₅ alkyl, haloand —OCH₃; and

n is selected from 1 and 2.

[8] In a more preferred embodiment, the present invention provides novelcompounds, wherein:

R¹ is phenyl substituted with 1-2 R^(1a);

R^(1a) is selected from para-halo and meta-halo;

A is phenyl substituted with 0-3 R⁵;

X is selected from —C(O)— and —S(O)₂—;

R⁵ is independently selected at each occurrence from C₁₋₅ alkyl, haloand —OCH₃; and

n is selected from 1 and 2.

[9] In a further more preferred embodiment, the present inventionprovides a compound selected from the group:

2-((1-(4-Fluorophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline,

2-((1-(3-Fluorophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline,

2-((1-(3-Fluorophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline,

2-((1-(4-Pyridylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydro-isoquinoline,

2-((1-(3-Pyridylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydro-isoquinoline,

2-((1-(4-Nitrophenylsulfonyl)-4-piperidyl))-1,2,3,4tetrahydroisoquinoline,

2-((1-(3-Nitrophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline,

2-((1-(2-Thienylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydro-isoquinoline,

2-((1-(3-Thienylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydro-isoquinoline,

1,3-Dihydro-2-((1-(3-thienylsulfonyl)-4-piperidyl)) isoindole,

1,3-Dihydro-2-((1-(2-thienylsulfonyl)-4-piperidyl)) isoindole,

1,3-Dihydro-2-((1-(4-fluorophenylsulfonyl)-4-piperidyl)) isoindole,

1,3-Dihydro-2-((1-(3-fluorophenylsulfonyl)-4-piperidyl)) isoindole,

1,3-Dihydro-2-((1-(4-nitrophenylsulfonyl)-4-piperidyl)) isoindole,

1,3-Dihydro-2-((1-(3-nitrophenylsulfonyl)-4-piperidyl)) isoindole,

1,3-Dihydro-2-((1-(4-pyridylsulfonyl)-4-piperidyl)) isoindole, and

1,3-Dihydro-2-((1-(3-pyridylsulfonyl)-4-piperidyl)) isoindole,

or a pharmaceutically acceptable salt form thereof.

[10] In a third embodiment, the present invention provides for a novelcompound of formula (III):

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein:

R¹ is selected from a C₆₋₁₀ carbocyclic aromatic residue substitutedwith 1-3 R^(1a), and a 5-10 membered aromatic heterocyclic systemcontaining from 1-4 heteroatoms selected from N, O and S, substitutedwith 0-2 R^(1a);

R^(1a) is independently selected at each occurrence from(CH₂)_(r)OR^(1d), halo, C₁₋₄ alkyl, (CH₂)_(r)—C₃₋₆ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, —CN, —NO₂, —OCF₃, (CH₂)_(r)NR^(1b)R^(1c),(CH₂)_(r)SO₂R^(1d), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)OR^(1d),(CH₂)_(r)OC(O)R^(1d), (CH₂)_(r)C(O)R^(1d), (CH₂)_(r)NR^(1b)C(O)R^(1c),(CH₂)_(r)C(O)NR^(1b)R^(1c), (CH₂)_(r)SR^(1d),(CH₂)_(r)CH(═NR^(1b))NR^(1b)R^(1c), (CH₂)_(r)SO₂NR^(1b)R^(1c),(CH₂)_(r)SO₂NR^(1b)R^(1c), (CH₂)_(r)(CF₂)_(r)CF₃ and (CH₂)_(r)-phenylsubstituted with 0-3 R^(1e);

R^(1b) and R^(1c) are independently selected at each occurrence fromhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and(CH₂)_(r)-phenyl substituted with 0-3 R^(1e);

R^(1d) is independently selected at each occurrence from C₁₋₆ alkyl and(CH₂)_(r)-phenyl substituted with 0-2 R^(1e);

R^(1e) is independently selected at each occurrence from H,—(CH₂)_(r)OR^(1f), halo, C₁₋₄ alkyl, CN, NO₂, and —CF₃;

R^(1f) is selected from hydrogen and C₁₋₅ alkyl;

R^(1g) is C₁₋₅ alkyl;

R⁴ is selected independently at each occurrence from hydrogen, C₁₋₆alkyl, (CH₂)_(r)—C₃₋₇ cycloalkyl, (CH₂)_(r)-aryl, and(CH₂)_(r)-heteroaryl;

R^(4a) is taken together with R¹ to form a 5 or 6- membered fusedheterocyclic ring containing 1-2 heteroatoms selected from O and Nsubstituted with 1 or 2 carbonyl groups;

R⁶ is selected independently at each occurrence from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(r)—C₃₋₆ cycloalkyl,(CH₂)_(r)-phenyl, —OH, —OC(O)R^(6a), C(O)R^(6a), C(O)OR^(6a);

R^(6a) is selected independently from C₁₋₆ alkyl, phenyl and benzyl;

R⁷ is selected from hydrogen and C₁₋₅ alkyl;

Y is C₁₋₃ alkylene;

A is selected from a 5 or 6 membered saturated, partially saturated orunsaturated ring which contains from 0-1 heteroatoms selected from N, Oand S, substituted with 0-3 R⁵, napthyl substituted with 0-3 R⁵, andnapthyl fused with ring B substituted with 0-3 R⁵;

R⁵ is selected independently at each occurrence from (CH₂)_(r)OR^(5d),halo, C₁₋₄ alkyl, (CH₂)_(r)—C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,—CN, —NO₂, —OCF₃, (CH₂)_(r)NR^(5b)R^(5c), (CH₂)_(r)SO₂R^(5d),(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)OR^(5d), (CH₂)_(r)OC(O)R^(5d),(CH₂)_(r)C(O)R^(5b), (CH₂)_(r)NR^(5b)C(O)R^(5c),(CH₂)_(r)C(O)NR^(5b)R^(5c), (CH₂)_(r)SR^(5d), (CH₂)_(r)CH(═NR^(5b))NR^(5b)R^(5c), (CH₂)_(r)SO₂NR^(5b)R^(5c), (CH₂)_(r)SO₂NR^(5b)R^(5c),(CH₂)_(r)(CF₂)_(r)CF₃ and (CH₂)_(r)-phenyl substituted with 0-3 R^(5e);

R^(5b) and R^(5c) are independently selected at each occurrence fromhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(r)-phenyl;

R^(5d) is independently selected at each occurrence from C₁₋₆ alkyl,phenyl substituted with 0-2 R^(5e), and benzyl substituted with 0-2R^(5e);

R^(5e) is independently selected at each occurrence from hydrogen,—(CH₂)_(r)OR^(5f), halo, C₁₋₄ alkyl, CN, NO₂, and —CF₃;

R^(5f) is selected from hydrogen and C₁₋₅ alkyl;

R^(5g) is C₁₋₅ alkyl;

n is selected from 1, 2, and 3;

r is selected from 0, 1, and 2; and

m is selected from 1, 2, and 3.

[11] In a preferred embodiment, the present invention provides for novelcompounds, wherein:

R¹ is phenyl substituted with 1-3 R^(1a);

R^(1a) is selected independently at each occurrence from halo, —CN, —CF₃and —CF₂CF₃;

Y is propylene;

A is selected from phenyl substituted with 0-3 R⁵, napthyl substitutedwith 0-3 R⁵ and napthyl fused to ring B substituted with 0-3 R⁵;

R⁵ is selected independently at each occurrence from C₁₋₅ alkyl, haloand —OCH₃;

n is selected from 1 and 2; and

m is 1.

[12] In a more preferred embodiment, the present invention provides fornovel compounds, wherein:

R¹ is phenyl substituted with 1-2 R^(1a);

R^(1a) is selected from para-halo and meta-halo;

A is phenyl substituted with 0-3 R⁵;

Y is C₁₋₃ alkylene;

R⁵ is independently selected at each occurrence from C₁₋₅ alkyl, haloand —OCH₃; and

n is selected from 1 and 2; and

m is 1.

[13] In a more preferred embodiment, the present invention provides fornovel compounds, wherein:

1,3-Dihydro-2-[3-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl))propyl]isoindole,

1,3-Dihydro-2-[3-((2-(4-bromophenyl)-1,3-dioxolan-2-yl))propyl]isoindole,

1,3-Dihydro-2-[3-((2-(4-methylphenyl)-1,3-dioxolan-2-yl))propyl]isoindole, and

2-[3-((2-(4-Fluorophenyl)-1,3-dioxolan-2-yl))propyl]-1,2,3,4-tetrahydroisoquinoline.

In a fourth embodiment, the present invention provides pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt form thereof.

In a fifth embodiment, the present invention provides a method oftreating a central nervous system disorder, including sleep disorders,depression and schizophrenia comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of formula(I), (II) or (III), or a pharmaceutically acceptable salt thereof.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(1a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(1a), thensaid group may optionally be substituted with up to two R^(1a) groupsand R^(1a) at each occurrence is selected independently from thedefinition of R^(1a). Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₆ alkyl”, is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl; “Alkenyl” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl, and the like.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 6- or 10-membered monocyclic or bicyclic aromaticcompound. Examples of such carbocycles include phenyl, indanyl, indenyland naphthyl.

As used herein, the term “aromatic heterocyclic system” or “aromaticheterocycle” is intended to mean a stable 5- to 7- membered monocyclicor bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ringwhich consists of carbon atoms and from 1 to 4 heterotams independentlyselected from the group consisting of N, O and S. It is preferred thatthe total number of S and O atoms in the aromatic heterocycle is notmore than 1.

Examples of such aromatic heterocyclic systems include, but are notlimited to, pyridyl, pyrimidyl, triazinyl, furanyl, quinolinyl,isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,isoxazolyl, pyrazolyl, triazolyl, tetrazolyl and indazolyl.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference. “Prodrugs” are intended to include anycovalently bonded carriers which release the active parent drugaccording to formula (I) in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of formula (I) are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of formula (I)wherein a hydroxy, amino, or sulfhydryl group is bonded to any groupthat, when the prodrug or compound of formula (I) is administered to amammalian subject, cleaves to form a free hydroxyl, free amino, or freesulfhydryl group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of alcohol andamine functional groups in the compounds of formula (I), and the like.Preferred prodrugs are amine prodrugs the amine group is attached to agroup selected from OH, C₁₋₄ alkoxy, C₆₋₁₀ aryloxy, C₁₋₄ alkoxycarbonyl,C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxyC₁₋₄ alkoxycarbonyl, and C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl. Morepreferred prodrugs are OH, methoxy, ethoxy, benzyloxycarbonyl,methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

SYNTHESIS

The compounds of Formula I can be prepared using the reactions andtechniques described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. Preferred methodsinclude, but are not limited to, those described below. All referencescited herein are hereby incorporated in their entirety herein byreference.

Some compounds of Formula 1 may be prepared, as shown in Scheme 1, bytreatment of an alkylating agent (1-1) with an amine (1-2) in thepresence of a base in an appropriate solvent.

Examples of useful alkylating agents (1-1) are those where LG is a goodleaving group, such as Cl, Br, I, alkylsulfonate, arylsulfonate, orperhaloalkylsulfonate. Useful bases include, but are not limited to, anexcess of amine (1-2) itself, metal carbonates such as K₂CO₃ or Cs₂CO₃,metal hydroxides such as NaOH or KOH, hindered alkoxides such aspotassium t-butoxide, or non-nucleophilic tertiary organic amines suchas N,N-diisopropylethylamine. These bases are required to absorb theacid H—LG which is liberated during the reaction. Typical solventsinclude polar aprotic liquids such as DMF or THF, or protic liquids suchas alcohols, including ethanol or isopropanol. It is known by thoseskilled in the art that the rates of alkylations of amines may beenhanced, particularly where LG is Cl or Br, by the addition of acatalytic amount of an iodide salt, such as NaI or KI, typically in theamount of 0.1 to 5 mole percent.

An alternate set of useful amine alkylation conditions utilize anorganic solvent which is poorly miscible with water, such as toluene ordichloromethane, and an aqueous solution of the base, particularly metalalkoxides, along with a phase transfer catalyst (PTC). Typical phasetransfer catalysts include tetraalkylammonium halides or hydroxides.

Alternatively, amine (1-1) may be initially converted into its conjugatebase by treatment with a strong base, such as n-butyllithium, in aninert solvent, typically THF, near or below ambient temperature under aninert atmosphere such as nitrogen or argon. The resulting amine amion isthen treated with alkylating agent (1—1), which may be introduced in aninert solvent.

In order to achieve useful reaction rates, any of the above reactions ofScheme 1 may require the application of heat from an external source.

The required alkylating agents (1—1), when not commercially available,are generally well known to those skilled in the art and are readilyprepared by usual methods. In certain instances, it may be advantageousto prepare reagents (1—1) in the same reaction vessel to be used for thealkylation without purification or isolation, before addition of theamine (1-2).

Many examples of the needed amine reagents (1-2) are commerciallyavailable or are known in the literature. When the desired amine (1-2)is new, a number of literature methods are generally applicable. Theseinclude, but are not limited to, reduction of amides or imides withborane (Gawley et al., J. Org. Chem. 1988, 53, 5381) or lithium aluminumhydride (Uffer et al., Helv. Chim. Acta 1948 31, 1397; Moffett, Org.Syn., Coll. Vol. IV 1963, 354).

An alternate sequence for the synthesis of some compounds of Formula 1is illustrated in Scheme 2.

An imide (2-1) is converted to its conjugate base by treatment with abase in an appropriate silvent, then allowed to react with alkylatingagent (1-1) described in Scheme 1. An alkyl imide (2-2) intermediate isformed and isolated. The conjugate base of imide (2-1) may be isolatedand purified in some instances, such as by precipitation by a non-polarsolvent followed by filtration. Useful bases include metal alkoxides andcarbonates. Alternatively, this conjugate base may be generated in situby mixing with a non-nucleophilic base either before or after theaddition of the alkylating agent (1-1).

The alkyl imide intermediate (2-2) is then converted to the amine (1) bytreatment with a reducing agent, such as borane or lithium aluminumhydride, in an appropriate solvent, typically THF.

It will be recognized by those skilled in the art that certainfunctional group substituents on reagents (1-1) or (2-1) may not becompatible with the strongly reducing conditions described in Step 2 ofScheme 2. In such instances, these functional groups may be carriedthrough the reaction sequence in a protected form, then released afterthe reduction reaction. The choice of protecting groups, and conditionsfor their introduction and subsequent removal, will be known to thoseskilled in the art, and are generally as described in Green and Wuts,Protective Groups in Organic Synthesis, 2nd Ed., Wiley and Sons, NY,1991.

Where convenient, some compounds of Formula (I) may be prepared as shownin Scheme 3.

Here, the functional group X—H of reagent (3-1) is converted into itsnucleophilic conjugate base by treatment with an appropriate base in auseful solvent, and allowed to react with an electrophile (3-2) whereinthe leaving group LG, as described above, is connected by linker group Yto the ring nitrogen. The ring nitrogen is rendered in non-nucleophilicform in (3-2) by its incorporation into an amide or imide functionalgroup as shown. The resulting amide or imide adduct (3-3) is thenreduced to the desired amine (1) as described in Scheme 2.

The choice of base for the first reaction of Scheme 3 is dependent onthe acidity of functional group X—H of (3-1). Where X—H of (3-1) isrelatively acidic, such as —S—H, a fairly weak base such as a metalcarbonate or hydroxide, is appropriate. For less acidic X—H such as—O—H, a stronger base such as metal hydride (e.g. sodium hydride) oralkyllithium will be useful.

The synthesis of the required electrophile (3-2) is by conversion ofamide or imide (2-1) to its conjugate base and treatment withbifunctional reagent LG—Y—LG, wherein LG is a leaving group as describedabove. The two leaving groups may be the same, in which case an excessof the reagent would be employed to statistically ensure monoadduct(3-2), or different, whereby a stoichiometric amount is acceptable andthe less reactive LG would remain in (3-2). In some instances theelectrophile (3-2) may be prepared in situ and not isolated or purified,but then allowed to react with nucleophile (3-1) as just described. Insuch an in situ preparation of the electrophile, it may be necessary topreform the conjugate base of reagent (3-1) in a separate reactionvessel, then transfer it into the vessel containing the electrophile.

Another method useful for the preparation of some compounds of Formula 1is shown in Scheme 4.

Amine (1-2) is condensed with an aldehyde or ketone (4-1) to form anenamine intermediate, which frequently is not isolated but is reduced insitu to form amine adduct (1). Many such reductive amination conditionsare well known in the chemical literature by those skilled in the art,and these are not further detailed here.

Another method for the preparation of some members of Formula 1 is givenin Scheme 5.

Amine (1-2) is condensed with carboxy compound (5-1) to form amide(5-2). The amide is then treated with a reducing agent, commonly boraneor lithium aluminum hydride as described earlier, to generate thedesired amine (1).

The carboxy group can be the parent carboxylic acid (Z is OH) in whichcase a coupling reagent must also be used. Many coupling reagents areknown in the literature for forming amide bonds from carboxylic acidsand amines; examples include, but are not limited to DCC, HBTU, TBTU,HATU, BOP, PyBOP, and alkyl chloroformates. Some of these couplingreagents, such as alkyl chloroformates, also require the presence of anon-nucleophilic base to consume the acid formed. Appropriate bases forsuch coupling reactions include tertiary amines such asN,N-diisopropylethylamine, triethylamine, or N-methylmorpholine. Undercoupling conditions such as these, the carboxy group is converted intoan activated species (Z is a leaving group) which is usually notisolated, but is allowed to react in situ with the amine partner (1-2).

Alternatively to the in situ activation of the carboxylic acid forcoupling, the acid can be converted into a relatively stable, activatedderivative which is isolable in pure form. Examples of this typeinclude, but are not limited to, formation of an acid halide (X is F,Cl, Br), an N-hydroxysuccinimide ester, or a pentafluorophenyl ester.Carboxylic acid pre-activating methods such as these are well known,especially in the peptide literature.

It will be recognized by those skilled in the art that one type offunctional group substituent on a compound of Formula 1 may be convertedinto another functional group by the appropriate chemical reaction at anadvantageous point in the synthetic sequence after the ring nitrogen tocarbon bond formation in the Schemes is complete. Of course, suchmanipulations must be chemically compatible with the newly formedtertiary amine present in the compound of Formula 1.

Typically, the free base amine products of Formula 1, once prepared, aretreated with an acid in an appropriate solvent to yield a salt adduct.These salt forms are often advantageous because they generally exhibitimproved crystallinity, formulatability, and water solubility relativeto the parent amines. Frequently, the salt adducts crystallize directlyfrom the salt formation solvent medium, and can be isolated byfiltration. In some cases, a co-solvent, usually of lesser polarity,must be added to induce crystallization.

The following examples further illustrate details for the preparation ofthe compounds of the present invention, and are not to be construed aslimiting the inventors scope. Those skilled in the art will readilyunderstand that known variations of the conditions and processes of thefollowing preparative procedures can alternatively be used to preparecompounds of the present invention. All temperatures are degreesCelsius.

EXAMPLES Example 1

1,3-Dihydro-2-[3-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1:1) maleic acid salt.

Method A: Part A:1,3-Dihydro-2-[3-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1AA).

1,3-Dihydroisoindole (Gawley et al., J. Org. Chem. 1988, 53, 5381) (1.19g, 10 mmol), 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (2.44g, 10 mmol), sodium iodide (10 mg), and potassium carbonate (1.52 g, 11mmol) were heated at reflux in MeOH (25 mL) for 8 days under nitrogen.After solvent removal in vacuo, the mixture was extracted with ethylacetate and water, then half-saturated brine. The solution was dried(magnesium sulfate), filtered, and concentrated to a brown oil. Thiscrude product was purified by flash chromatography on silica gel 60,eluting with a gradient of hexane to ethyl acetate. Solvent removal invacuo gave 1AA as a brown oil (0.50 g). MS (CI, NH₃) m/e 328 (base,M+H⁺).

Method A: Part B: 11,3-Dihydro-2-[3-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1:1) maleic acid salt

A solution of maleic acid (0.18 g, 1.6 mmol) in THF (5 mL) was added toa solution of the Part A amine 1AA (0.48 g, 1.5 mmol) with stirring atroom temperature (RT). The resulting clear solution was diluted withdiethyl ether to generate a solid. The solid was collected byfiltration, rinsed, and dried to yield 1 (0.49 g). m.p. 141-142° C.Elemental analysis. Calc'd for C₂₄H₂₆FNO₆: C, 65.00; H, 5.91; N, 3.16.Found: C, 64.79; H, 5.96; N, 3.09. H NMR(300 MHz, CDCl₃, δ): 7.42-7.28(m, 6H), 7.06-7.00 (m, 2H), 6.23 (s, 2H), 5.20-4.20 (v br, 4H),4.05-4.00 (m, 2H), 3.78-3.73 (m, 2H), 3.33-3.28 (m, 2H), 2.00-1.89 (m,4H), 1.60 (v br, 2H).

Method B:1,3-Dihydro-2-[3-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1AA).

1,3-Dihydroisoindole (5.0 g, 85% pure, 36 mmol),2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (7.4 mL, 36 mmol),potassium iodide (66 mg), and powdered potassium carbonate (5.5 g, 40mmol) were heated to 55° C. in DMF (20 mL) for 4 days under nitrogen.Extractive work-up followed by flash chromatography as in Method A, PartA gave the same brown oil 1AA (4.4 g). The oil eventually solidifiedupon standing.

Method C:1,3-Dihydro-2-[3-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1AA).

n-Butyllithium (2.5 M in hexanes, 34 mL, 84 mmol) was added dropwiseover 10 min to a −50° solution of 1,3-dihydroisoindole (10.8 g, 93%pure, 84 mmol) in dry THF (400 mL) with stirring under nitrogen. After 1h, 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (16 mL, 80 mmol)was added, followed by a few mg of sodium iodide. The reaction wasallowed to slowly warm and stir at RT overnight. The crude reactionmixture was preabsorbed onto silica gel 60 (150 g) by concentration invacuo, then loaded on top of a silica gel flash column and eluted asabove. The purest fractions were combined and evaporated to yield thesame desired amine 1AA (3.3 g) as a dark solid.

Method D: Part A:N-[3-((2-(4-Fluorophenyl)-1,3-dioxolan-2-yl))propyl]phthalimide (1DA).

Potassium phthalimide (37 g, 200 mmol),2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (50 g, 200 mmol),and sodium iodide (0.2 g) were stirred in DMF (200 mL) under nitrogenwith heating to 83° C. After 18.75 h, the reaction was concentrated invacuo. After extractive work-up (ethyl acetate/water, then brine),drying (sodium sulfate), filtration, and concentration, the crude solidproduct was purified by recrystallization from boiling abs. EtOH (700mL). The resulting solid was collected by filtration, rinsed, and driedunder high vacuum at 70° C. to yield the imide adduct IDA (56.5 g) ascolorless needles. m.p. 151-152° C. Elemental analysis. Calc'd forC₂₀OH₁₈FNO₄: C, 67.60; H, 5.12; N, 3.94; F, 5.36. Found: C, 67.36; H,4.90; N, 3.88; F, 5.39. ¹H NMR(300 MHz, CDCl₃, δ): 7.84-7.80 (m, 2H),7.73-7.69 (m, 2H), 7.42-7.37 (m, 2H), 7.02-6.96 (m, 2H), 4.05-3.94 (m,2H), 3.79-3.67 (m, 4H), 1.96-1.91 (m, 2H), 1.80-1.70 (m, 2H). C NMR(300MHz, CDCl₃, δ): 168.29, 162.43 (d, J=246 Hz), 138.29, 133.79, 132.14,127.46 (d, J=9 Hz), 123.09, 114.94 (d, J=21 Hz), 109.67, 64.57, 37.90,37.74, 22.92. IR(KBr, cm⁻¹): 1770 (m), 1716 (s), 1704 (s). UV(MeOH):λmax 293 nm, ε 2300; λmax 268 nm, ε 1600; λmax 262 nm, ε 1500; λmax 241nm, ε 12,000; λmax 220 nm, ε 49,000. ). MS (CI, NH₃) m/e 373 (base,M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 356.1298. Found: 356.1319.

Method D: Part B:1,3-Dihydro-2-[3-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1AA).

Imide 1DA (56.3 g, 160 mmol) and lithium aluminum hydride pellets (26 g,640 mmol) were boiled in dry THF (1L) with mechanical stirring undernitrogen. After 22 h, ¹H NMR analysis of an aliquot revealed incompletereaction, so more LiAlH₄ (7.6 g) was added. The mixture was boiledanother 16.5 h, then cooled to RT. Celite was slurried into the reactionmixture, which was then quenched by portionwise addition of Na₂SO₄·10H₂O(160 g) with vigorous stirring. Tetrahydrofuran was added periodicallyto maintain efficient stirring during the quenching. After gas evolutionhad ceased the mixture was filtered through additional Celite and rinsedwell with THF and EtOAc. Flash chromatographic purification yielded thedesired amine 1AA (43 g) as a brown solid of good purity.

Instead of chromatographic purification, the crude amine product wasalternately purified by converting to the maleic acid salt as usual,recrystallizing from boiling isopropanol, and filtering to produce 1 in41% overall yield of excellent purity from IDA.

Example 2

1,3-Dihydro-2-[3-((2-(4-bromophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1:1) maleic acid salt.

Part A: 2-(3-Chloropropyl)-2-(4-bromophenyl)-1,3-dioxolane (2A).

4′-Bromo-4-chlorobutyrophenone (25 g, 96 mmol), ethylene glycol (5.9 mL,105 mmol), and p-toluenesulfonic acid monohydrate (50 mg) were heated toreflux in benzene (100 mL) under a Dean-Stark trap under nitrogen for 21h. After cooling, half saturated aq. NaHCO₃ (50 mL) was added and themixture extracted with EtOAc. The organic phase was extracted furtherwith water, then brine, dried (Na₂SO₄), filtered, concentrated, andKugelrohr distilled, bp (oven T) 126-146° C. (1.1 mm Hg) to yield 2A(26.4 g) as a colorless liquid. Elemental analysis. Calc'd forC₁₂H₁₄BrClO₂: C, 47.16; H, 4.63; Cl, 11.60; Br, 26.15. Found: C, 47.24;H, 4.51; Cl, 11.67; Br, 26.31. ¹H NMR(300 MHz, CDCl₃, δ): 7.48 (d, 2H,J=8 Hz), 7.33 (d, 2H, J=8 Hz), 4.08-3.96 (m, 2H), 3.81-3.69 (m, 2H),3.53 (t, 2H, J=7 Hz), 2.10-1.98 (m, 2H), 1.91-1.80 (m, 2H). ¹³C NMR(300MHz, CDCl₃, δ): 141.48, 131.34, 127.53, 122.09, 109.62, 64.62, 45.00,37.62, 26.93. IR(KBr, cm⁻¹): 1740 (w), 1688 (w), 1590 (m), 1072 (s),1042 (s), 1010 (s). UV(MeOH): λmax 257 nm, ε 720; λmax 220 nm, ε 10,650.). MS (CI, NH₃) m/e 307 (base, M+H⁺, 1 Br+1 C1 isotope pattern), 227(37%). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 304.9944. Found: 304.9956.

Part B:1,3-Dihydro-2-[3-((2-(4-bromophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(2B).

1,3-Dihydroisoindole was treated with chloride 2A under conditions ofExample 1, Method B, except no KI was used and the bath T was 75-80° C.The amine 2B was isolated after flash chromatographic purification as abrown solid (38% yield). MS (CI, NH³) m/e 388 (base, M+H⁺, 1 Br isotopepattern). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 390.0892. Found:390.0895.

Part C:1,3-Dihydro-2-[3-((2-(4-bromophenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1:1) maleic acid salt (2).

A solution of maleic acid (0.21 g, 1.8 mmol) was added to a solution ofamine 2B (1.0 g, 70% pure, 1.8 mmol) in THF (20 mL) with stirring at RT.The resulting salt precipitate was collected by filtration, rinsed, anddried, then recrystallized from boiling abs. EtOH to yield 2 (0.47 g) ascolorless flakes. m.p. 1720 (dec). Elemental analysis. Calc'd forC₂₄H₂₆BrNO₆: C, 57.15; H, 5.21; N, 2.79; Br, 15.84. Found: C, 56.85; H,5.21; N, 2.63; Br, 15.99. ¹H NMR(300 MHz, DMSO-d₆, δ): 7.59 (d, 2H, J=8Hz), 7.41-7.35 (m, 6H), 6.03 (s, 2H), 4.60 (br s, 2H), 4.08-3.96 (m,2H), 3.76-3.65 (m, 2H), 3.38-3.33 (m, 2H), 1.94-1.89 (m, 2H), 1.74-1.64(m, 2H). ¹³C NMR(300 MHz, DMSO-d₆, δ): 167.70, 141.94, 136.31, 135.02,131.66, 128.88, 128.27, 123.29, 121.83, 109.29, 64.88, 58.35, 54.35,36.70, 20.55. IR(KBr, cm⁻¹: 2800-2300 (m, br), 1704 (m), 1484 (s), 1466(s). UV(MeOH): λmax 270 nm, ε 1055; λmax 264 nm, ε 1322; λmax 257 nm, ε1296. MS (CI, NH₃) m/e 388 (base, M+H⁺, 1 Br isotope pattern). HRMS(CI,NH₃) m/e Calc'd for (M+H⁺, ⁸¹Br isotope): 390.0892. Found: 390.0887.

Example 3

1,3-Dihydro-2-[3-((2-(4-methylphenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1:1) maleic acid salt

Part A: 2-(3-Chloropropyl)-2-(4-methylphenyl)-1,3-dioxolane (3A).

4′-Methyl-4-chlorobutyrophenone was converted to ketal 3A (99% yield) asa colorless liquid under conditions analogous to Example 2, Part A. B.p.(oven T) 110-130° C. (1.1 mm Hg). Elemental analysis. Calc'd forC₁₃H₁₇ClO₂: C, 64.86; H, 7.13; Cl, 14.73. Found: C, 65.23; H, 6.97; Cl,14.43. H NMR(300 MHz, CDCl₃, δ): 7.33 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8Hz), 4.05-3.94 (m, 2H), 3.82-3.71 (m, 2H), 3.51 (t, 2H, J=7 Hz), 2.34(s, 3H), 2.04-1.99 (m, 2H), 1.87-1.80 (m, 2H). ¹³C NMR(300 MHz, CDCl₃,δ): 139.30, 137.65, 128.88, 125.60, 110.05, 64.51, 45.17, 37.81, 27.14,21.12.

Part B:1,3-Dihydro-2-[3-((2-(4-methylphenyl)-1,3-dioxolan-2-yl))propyl]isoindole(3B).

Prepared from chloride 3A and 1,3-dihydroisoindole analogously toExample 2B. Yield amine 3B (26% yield) as a brown viscous oil. . MS (CI,NH₃) m/e 324 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺):324.1964. Found: 324.1950.

Part C:1,3-Dihydro-2-[3-((2-(4-methylphenyl)-1,3-dioxolan-2-yl))propyl]isoindole(1:1) maleic acid salt (3).

The salt was prepared analogously to Example 1, Method A, Part B toyield 3 (50% yield) as off-white flakes. m.p. 159-161 ° C (dec.).Elemental analysis. Calc'd for C₂₅H₂₉NO₆: C, 68.32; H, 6.65; N, 3.20.Found: C, 68.07; H, 6.72; N, 3.08. ¹H NMR(300 MHz, DMSO-d₆, δ):7.41-7.34 (m, 4H), 7.30 (d, 2H, J=8Hz), 7.19 (d, 2H, J=8Hz), 6.03 (s,2H), 4.57 (br s, 4H), 4.05-3.94 (m, 2H), 3.74-3.63 (m, 2H), 3.37-3.31(m, 2H), 2.30 (s, 3H), 1.93-1.88 (m, 2H), 1.74-1.63 (m, 2H). ¹³C NMR(300MHz, DMSO-d₆, δ): 167.65, 139.50, 137.61, 136.26, 134.94, 129.20,128.84, 125.77, 123.24, 109.60, 64.64, 58.33, 54.42, 36.88, 21.10,20.59. IR(KBr, cm⁻¹): 3434 (w, br), 2632-2398 (m-s), 1574 (s), 1500 (s).UV(MeOH): λmax 270 nm, ε 1290; λmax 263 nm, ε 1560; λmax 256 nm, ε 1520.MS (CI, NH₃) m/e 324 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺):324.1964. Found: 324.1966.

Example 4

2-[3-((2-(4-Fluorophenyl)-1,3-dioxolan-2-yl))propyl]-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt.

Part A:2-[3-((2-(4-Fluorophenyl)-1,3-dioxolan-2-yl))propyl]-1,2,3,4-tetrahydroisoquinoline(4A)

1,2,3,4-Tetrahydroisoquinoline, n-BuLi, and2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane were allowed toreact under conditions analogous to Example 1, Method C. Flashchromatographic purification provided 4A (16% yield) as a yellow oil. ¹HNMR(300 MHz, CDCl₃, δ): 7.44-7.39 (m, 2H), 7.15-6.98 (m, 6H), 4.08-3.96(m, 2H), 3.83-3.71 (m, 2H), 3.57 (s, 2H), 2.87 (t, 2H, J=6 Hz), 2.67 (t,2H, J=6 Hz), 2.47 (t, 2H, J 7 Hz), 1.96-1.91 (m, 2H), 1.69-1.59 (m, 2H).

Part B:2-[3-((2-(4-Fluorophenyl)-1,3-dioxolan-2-yl))propyl]-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt (4)

Amine 4A (4.4 g) was converted to its maleic acid salt in the usualfashion to produce a colorless powder 4 (4.9 g). m.p. 160-162° C.Elemental analysis. Calc'd for C₂₅H₂₈FNO₆: C, 65.63; H, 6.18; N, 3.06;F, 4.15. Found: C, 65.69; H, 6.23; N, 3.02; F, 4.30. ¹H NMR(300 MHz,DMSO-d₆, δ): 7.44-7.40 (m, 2H), 7.23-7.13 (m, 6H), 6.01 (s, 2H), 4.35(br s, 2H), 4.04-3.92 (m, 2H), 3.73-3.62 (m, 2H), 3.44 (br s, 2H),3.20-3.15 (m, 2H), 3.05-2.98 (m, 2H), 1.91-1.74 (m, 4H). ¹³C NMR(300MHz, DMSO-d₆, δ): 167.71, 162.29 (d, J=244 Hz), 138.81, 136.26, 131.74,129.04, 128.95, 128.09, 127.97, 127.04 (d, J=4 Hz), 115.39 (d, J=21 Hz),109.31, 64.78, 55.68, 52.59, 49.50, 36.97, 25.50, 18.88. IR(KBr, cm⁻¹):2800-2336 (m-s, br), 1576 (s), 1506 (s). UV(MeOH): λmax 268 nm, ε 860;λmax 262 nm, ε 1100; λmax 255 nm, ε 1000. MS (CI, NH₃) m/e 342 (base,M+H³⁰ ). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 342.1869. Found: 342.1870.

Example 5

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) isoindole (1:1) maleicacid salt.

Part A: 1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))isoindole (5A).

Ketal 1AA (3.3 g, 10 mmol) and 1 M aq. HCl (15 mL) were stirred in MeOH(60 mL) at RT for 2 days. The reaction mixture was combined with another(0.6 g of 1AA) for work-up. The MeOH was evaporated in vacuo. Theremainder was extracted with EtOAc (250 mL) and 1 M aq. NaOH (30 mL),then H₂O (25 mL), and brine (10 mL). After drying (Na₂SO₄) andconcentration, the product was purified by flash chromatography, elutingwith a gradient of hexane to EtOAc to 20% MeOH in EtOAc. Concentrationand drying in vacuo produced the amino ketone 5A as a brown solid inquantitative yield. ¹H NMR(300 MHz, CDCl₃, δ): 8.02-7.97 (m, 2H), 7.19(s, 4H), 7.17-7.08 (m, 2H), 3.93 (s, 4H), 3.09 (t, 2H, J=7 Hz), 2.82 (t,2H, J=7 Hz), 2.03 (pentet, 2H, J=7 Hz). IR(KBr, cm⁻¹): 1682 (s), 1598(s), 1506 (m), 1234 (s), 1156 (s), 744 (s). UV(MeOH): λmax 331 nm, ε1200; λmax 272 nm, ε 2400; λmax 243 nm, ε 14,000. MS (CI, NH₃) m/e 284(base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 284.1451. Found:284.1435.

Part B: 1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) isoindole (1:1)maleic acid salt (5).

Standard procedure from 5A. m.p. 114-115° C. Elemental analysis. Calc'dfor C₂₂H₂₂FNO₅: C, 66.16; H, 5.55; N, 3.52; F, 4.77. Found: C, 66.17; H,5.56; N, 3.50; F, 4.67. ¹H NMR(300 MHz, DMSO-d₆, δ): 8.10-8.04 (m, 2H),7.45-7.35 (m, 6H), 6.05 (s, 2H), 4.70 (br s, 4H), 3.45 (t, 2H, J=8 Hz),3.24 (t, 2H, J=7 Hz), 2.12-2.02 (m, 2H). ¹³C NMR(300 MHz, DMSO-d₆, δ):197.70, 167.71, 165.50 (d, J=252 Hz), 136.18, 135.05, 133.62, 131.31 (d,J=10 Hz), 128.85, 123.26, 116.16, 58.38, 54.01, 35.14, 20.26. IR(KBr,cm⁻¹): 3440 (w, br), 2800-2300 (m-s, br), 1684 (s), 1598 (s), 1576 (s).UV(MeOH): λmax 243 nm, ε 9200. MS (CI, NH₃) m/e 284 (base, M+H ).HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 284.1451. Found: 284.1469.

Example 6

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) isoindole (1:1)hydrochloric acid salt.

1,3-Dihydroisoindole hydrochloride (35 g, 220 mmol),4-chloro-(4′-fluoro)butyrophenone (44 g, 220 mmol),N,N-diisopropylethylamine (78 mL, 450 mmol), and NaI (200 mg) wereheated to 95°in DMF (220 mL) with stirring under N₂ for 3 days. Afterconcentration in vacuo, the mixture was extracted with EtOAc (3 L) and 1M NaOH (500 mL), then H₂O (5×500 mL), and brine (300 mL). The mixturewas dried (Na₂SO₄), filtered, concentrated, and flash chromatographedwith gradient elution hexane to EtOAc to 2% MeOH in EtOAc. All majorproduct containing fractions were combined and concentrated to yield 5A(26.2 g) as a brown solid of 75% purity (estimated by ¹H NMR). Thisamine SA was purified by conversion to its hydrochloride salt asfollows.

1.0 M HCl/Et₂O (125 mL) was added to a solution of amine 5A (26 g, ca.93 mmol) in CH₂Cl₂ (100 mL). The resulting solid was diluted with Et₂Oand collected by filtration. The purity of the product salt was upgradedby sequentially recrystallizing from boiling benzene, then MeOH/Et₂O(2×) to yield a pale grey powder 6 (16.4 g). m.p. 174-175° C. Elementalanalysis. Calc'd for C₁₈H₁₉FClNO: C, 67.60; H, 6.00; N, 4.39; F, 5.94;Cl, 11.09. Found: C, 67.62; H, 5.99; N, 4.28; F, 5.93; Cl, 10.96. ¹HNMR(300 MHz, DMSO-d₆, δ): 11.35 (br s, 1H), 8.10-8.05 (m, 2H), 7.43-7.36(m, 6H), 4.82 (br s, 2H), 4.54 (br s, 2H), 3.45-3.40 (br t, 2H, J=8 Hz),3.25 (t, 2H, J=7 Hz), 2.07 (pentet, 2H, J=8 Hz). ¹³C NMR(300 MHz,DMSO-d₆, δ): 197.76, 165.48 (d, J=251 Hz), 134.85, 133.63, 131.34 (d,J=10 Hz), 128.75, 123.19, 116.14 (d, J=22 Hz), 57.90, 53.94, 35.66,19.95. IR(KBr, cm⁻¹): 2800-2400 (m, br), 1684 (s), 1598 (s). UV(MeOH):λmax 244 nm, ε 15,000. MS (CI, NH₃) m/e 284 (base, M+H⁺). HRMS(CI, NH₃)m/e Calc'd for (M+H⁺): 284.1451. Found: 284.1452.

Example 7

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) isoindole (1:1)methanesulfonic acid salt.

Methanesulfonic acid (6.3 g, 65 mmol) was added to a solution of amine5A (18.5 g, 65 mmol) in CH₂Cl₂ with stirring at RT. After solventremoval in vacuo, the crude salt was recrystallized twice from boiling2-propanol to yield 7 (11.8 g) as pale grey flakes. m.p. 145-150° C.Elemental analysis. Calc'd for C₁₉H₂₂FNO₄S: C, 60.14; H, 5.84; N, 3.69;F, 5.02; S, 8.45. Found: C, 60.17; H, 5.82; N, 3.59; F, 5.02; S, 8.45.¹H NMR(300 MHz, DMSO-d₆, δ): 10.64 (br s, 1H), 8.07-8.03 (m, 2H),7.41-7.31 (m, 6H), 4.95-4.55 (v br s, 4H), 3.45 (br t, 2H, J=8 Hz), 3.21(t, 2H, J=7 Hz), 2.28 (s, 3H), 2.05 (pentet, 2H, J=8 Hz). ¹³C NMR(300MHz, DMSO-d₆, δ): 197.73, 165.51 (d, J=251 Hz), 134.79, 133.57, 131.36(d, J=10 Hz), 128.89, 123.29, 116.16 (d, J=21 Hz), 58.35, 54.01, 35.24,20.10. IR(KBr, cm⁻¹): 3600-2400 (w-s, br), 1684 (s), 1598 (m), 1226 (s),1208 (s), 1192 (s). UV(MeOH): λmax 244 nm, ε 15,000. MS (CI, NH₃) m/e284 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H ): 284.1451. Found:284.1438.

Example 8

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) isoindole (1:1) fumaricacid salt.

Fumaric acid (9.1 g, 78 mmol) was added to a solution of amine 5A (22.2g, 78 mmol) in CH₂Cl₂ (100 mL) with stirring at RT. After solventremoval in vacuo, the crude salt was stirred in Et₂O (500 mL) breakingthe solid chunks into small pieces with a spatula, then filtered. Theresulting solid was recrystallized twice from boiling 2-propanol toyield 8 (12 g) as pale brown needles. m.p. 156-158° C. Elementalanalysis, sample dried further by analyst. Calc'd for C₂₂H₂₂FNO5: C,66.16; H, 5.55; N, 3.52; F, 4.77. Found: C, 66.42; H, 5.53; N, 3.32; F,4.91. ¹H NMR(300 MHz, DMSO-d₆, δ): 8.07-8.01 (m, 2H), 7.37-7.29 (m, 2H),7.26-7.18 (m, 4H), 6.60 (s, 2H), 3.94 (s, 4H), 3.11 (t, 2H, J=7 Hz),2.81 (t, 2H, J=7 Hz), 1.89 (pentet, 2H, J=7 Hz). ¹³C NMR(300 MHz,DMSO-d₆, δ): 198.21, 167.60, 165.37 (d, J=251 Hz), 137.89, 134.96,133.77, 131.21 (d, J=9 Hz), 127.76, 122.84, 116.03 (d, J=21 Hz), 58.18,54.39, 35.66, 21.73. IR(KBr, cm⁻¹): 2638-2390 (m, br), 1684 (s), 1598(s). UV(MeOH): λmax 243 nm, ε 19,000. MS (CI, NH₃) m/e 284 (base, M+H⁺).HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 284.1451. Found: 284.1458.

Example 9

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-hydroxybutyl)) isoindole (1:1)maleic acid salt

Part A: 1,3-Dihydro-2-((4-(4-fluorophenyl)-4-hydroxybutyl)) isoindole(9A).

Sodium borohydride (0.26 g, 7.0 mmol) was added in two equal portionsover 1.57 h to a solution of aminoketone 5A (1.0 g, 3.5 mmol) in MeOH(10 mL) with stirring at RT. After 70 min more, the solvent wasevaporated in vacuo to yield alcohol 9A (1.03 g) as a brown gum. ¹HNMR(300 MHz, CDCl₃, δ): 7.36-7.31 (m, 2H), 7.20 (s, 4H), 7.02-6.96 (m,2H), 4.74-4.66 (m, 1H), 4.03 and 3.96 (AB quartet, 4H, J=12 Hz),2.86-2.83 (m, 2H), 2.03-1.76 (m, 4H). IR(KBr, cm⁻¹): 3370 (m, br), 1604,(m), 1508 (s), 1220 (s), 836 (s), 744 (s).

Part B: 1,3-Dihydro-2-((4-(4-fluorophenyl)-4-hydroxybutyl)) isoindole(1:1) maleic acid salt (9)

Aminoalcohol 9A was converted to the 1:1 maleic acid salt in the usualway and dried under high vacuum at 56° C. to yield 9 as a grey powder.m.p. 113-114° C. Elemental analysis. Calc'd for C₂₂H₂₄FNO₅: C, 65.82; H,6.04; N, 3.50; F, 4.73. Found: C, 65.68; H, 6.06; N, 3.46; F, 4.43. ¹HNMR(300 MHz, DMSO-d₆, δ): 7.38-7.35 (m, 6H), 7.12 (t, 2H, J=9 Hz), 6.02(s, 2H), 4.704.52 (br s, 5H), 3.36-3.34 (m, 2H), 1.74-1.64 (m, 4H). ¹³CNMR(300 MHz, DMSO-d₆, δ): 167.72, 161.55 (d, J=242 Hz), 142.42, 136.21,134.88, 128.87, 128.04 (d, J=8 Hz), 123.26, 115.14 (d, J=21 Hz), 71.31,58.31, 54.53, 36.27, 22.31. IR(KBr, cm⁻¹): 3368 (m, br), 2750-2300 (m,br), 1576 (s), 1508 (s). UV(MeOH): λmax 270 nm, ε 2100; λmax 264 nm, ε2300;λmax 257 nm, ε 2000. MS (CI, CH₄) m/e 286 (base, M+H⁺), 268 (45%,M+H⁺−H₂O), 190 (23%). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 286.1607.Found: 286.1603.

Example 10

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-acetoxybutyl)) isoindole (1:1)maleic acid salt.

Hydroxyamine 9A (0.52 g, 1.8 mmol), acetic anhydride (0.17 mL, 1.8mmol), and Et3N (0.25 mL, 1.8 mmol) were stirred at RT in CHCl₃ (5 mL)containing a catalytic amount of 4-DMAP for 24 h. Solvent was evaporatedin vacuo and the residue was extracted with EtOAc (50 mL) and 1 M NaOH(6 mL), H₂O (5 mL), and brine (5 mL). The solution was dried (Na₂SO₄),filtered, and concentrated to yield the acetate as a brown solid. Thecrude product was directly converted to its maleic acid salt as usual toprovide 10 (0.51 g) as a grey amorphous solid. m.p. 92-95° C. (dec.).Elemental analysis. Calc'd for C₂₄H₂₆FNO₆: C, 65.00; H, 5.92; N, 3.17;F, 4.28. Found: C, 64.92; H, 5.92; N, 3.03; F, 4.12. ¹H NMR(300 MHz,DMSO-d₆, δ): 7.46-7.38 (m, 6H), 7.22 (t, 2H, J=9 Hz), 6.06 (s, 2H),5.76-5.71 (m, 1H), 4.63 (br s, 4H), 3.42-3.37 (m, 2H), 2.08 (s, 3H),2.00-1.66 (m, 4H). ¹³C NMR(300 MHz, DMSO-d₆, δ): 170.17, 167.70, 161.62(d, J=244 Hz), 136.94, 136.17, 134.96, 128.84, 128.78 (d, J=8 Hz),123.23, 115.69 (d, J=21 Hz), 74.34, 58.32, 54.02, 32.99, 22.05, 21.34.IR(KBr, cm⁻¹) : 2800-2400 (m-s, br), 1728 (s), 1574 (s), 1514 (s), 1234(s), 1222 (s). UV(MeOH): λmax 270 nm, ε 1800; λmax 263 nm, ε 2000; λmax257 nm, ε 1800. MS (CI, CH₄) m/e 328 (42%, M+H⁺), 268 (base), 107 (25%).HRMS(CI, NH₃) m/e Calc'd for M+H⁺): 328.1713. Found: 328.1696.

Example 11

2-((4-(4-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline (1:1)maleic acid salt.

Method A, Part A:2-((4-(4-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline(11A).

Dioxolane 4A (2.75 g, 6.0 mmol) and 1 M HCl (15 mL) were stirred in MeOH(50 mL) at RT for 3 days. After concentration in vacuo the residue wasextracted with EtOAc (400 mL) and 1 M NaOH (100 mL), then H₂O (2×50 mL),and brine (25 mL). The solution was dried (Na₂SO₄), filtered, andconcentrated to yield ketone 11A (1.9 g, quant.) as a yellow solid. ¹³CNMR(300 MHz, CDCl₃, δ): 198.60, 165.59 (d, J=254 Hz), 134.85, 134.38,133.56, 131.65 (d, J=9 Hz), 128.61, 126.56, 126.08, 125.56, 115.52 (d,J=22 Hz), 57.36, 56.08, 50.87, 36.14, 29.12, 21.79.

Method A, Part B:2-((4-(4-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline (1:1)maleic acid salt (11).

Aminoketone 11A (1.9 g) was converted to its maleic acid salt as usualto provide 11 (2.4 g) as a colorless solid. m.p. 129-130° C. Elementalanalysis. Calc'd for C₂₃H₂₄FNO₅: C, 66.82; H, 5.85; N, 3.40; F, 4.61.Found: C, 66.46; H, 5.62; N, 3.27; F, 4.64. ¹H NMR(300 MHz, DMSO-d₆, δ):8.10-8.03 (m, 2H), 7.43-7.21 (m, 6H), 6.03 (s, 2H), 4.41 (br s, 2H),3.63-3.10 (m, 8H), 2.14-2.04 (m, 2H). ¹³C NMR(300 MHz, DMSO-d₆, δ):197.75, 167.70, 165.50 (d, J=252 Hz), 136.20, 133.59, 131.83, 131.31 (d,J=9 Hz), 129.17, 128.14, 127.13, 127.07, 116.15 (d, J=21 Hz), 55.24,52.81, 49.49, 35.26, 25.52, 18.75. IR(KBr, cm⁻¹): 3600-2400 (m-s, br),1690 (s), 1596 (s), 1506 (s). UV(MeOH): λmax 243 nm, ε 16,000. MS (ESI)m/e 298 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 298.1607.Found: 298.1599.

Method B, Part A:2-((4-(4-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline(11A).

Aminoketone 11A was alternatively synthesized in a single step fromcommercial reagents 4-chloro-4′-fluorobutyrophenone,1,2,3,4-tetrahydroisoquinoline, N,N-diisopropylethylamine, and catalyticNaI in DMF in similar fashion to Example 6. Flash chromatographicpurification, eluting with a gradient of hexane to EtOAc provided thesame aminoketone 11A (49% yield) as a solid. m.p. 69-71° C. Additional11A was recovered in mixed column fractions which could be furtherpurified to improve the total yield.

Example 12

1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))benz[f]isoindole (1:1)maleic acid salt.

Part A: 1,3-Dihydrobenz[f]isoindole (12A).

2,3-Naphthalene dicarboximide (5.0 g, 25 mmol) was reduced with BH₃-THF(1 M in THF, 100 mL, 100 mmol) according to the Gawley method used for1,3-dihydroisoindole in Example 1, Method A, Part A. The crude productwas purified by flash chromatography on silica gel 60, eluting with agradient of 2% to 10% MeOH in CHCl₃ to produce 12A (1.8 g, 43%) as asolid. m.p. 127-129° C. ¹H NMR(300 MHz, MeOH-d₄, δ): 7.80-7.72 (m, 2H),7.71 (s, 1H), 7.42-7.38 (m, 2H), 4.32 (s, 4H). MS (GC/MS, H₂₀) m/e 170(base, M+H⁺).

Part B: 1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) benz[f]isoindole(12B).

Amine 12A was alkylated with 4-chloro-41-fluoro butyrophenoneanalogously to Example 6. The crude product was purified by flashchromatography on silica gel 60, eluting with 1:1 EtOAc/hexane to yieldaminoketone 12B (39% yield) as a brown solid. m.p. 148-149° C. ¹HNMR(300 MHz, CDCl₃, δ): 7.98-7.93 (m, 2H), 7.78-7.73 (m, 2H), 7.58 (s,2H), 7.42-7.35 (m, 2H), 7.06 (t, 2H, J=9 Hz), 3.98 (s, 4H), 3.06 (t, 2H,J=7 Hz), 2.81 (t, 2H, J=7 Hz), 2.09-2.00 (m, 2H). ¹³C NMR(300 MHz,CDCl₃, δ): 198.47, 165.60 (d), 139.14, 133.60 (d), 133.03, 130.60 (d),127.74, 125.29, 120.37, 115.50 (d), 58.57, 55.35, 36.04, 23.35. IR(KBr,cm⁻¹): 1686 (s). MS (CI, NH₃) m/e 334 (base, M+H⁺). HRMS(CI, NH₃) m/eCalc'd for (M+H⁺): 334.1607. Found: 334.1623.

Part C: 1,3-Dihydro-2-( (4-(4-fluorophenyl)-4-oxobutyl))benz[f]isoindole(1:1) maleic acid salt (12).

Method from 12B. Recrystallized from boiling isopropanol to producesolid 12. m.p. 157-158° C. Elemental analysis. Calc'd for C₂₆H₂₄FNO₅: C,69.48; H, 5.38; N, 3.13; F, 4.24. Found: C, 69.81; H, 5.40; N, 2.98; F,4.30. ¹H NMR(300 MHz, DMSO-d₆, δ): 8.10-8.05 (m, 2H), 7.95-7.85 (m, 4H),7.55-7.50 (m, 2H), 7.22 (t, 2H, J=9 Hz), 6.20 (s, 2H), 4.90 (s, 4H),3.60-3.52 (m, 2H), 3.25 (t, 2H, J=6 Hz), 2.30-2.19 (m, 2H). IR(KBr,cm⁻¹): 3600-2400 (m-s, br), 1684 (s). MS (CI, NH₃) m/e 334 (base, M+H⁺).HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 334.1607. Found: 334.1610.

Example 13

2-((4-(4-Pyridyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline (1:1)maleic acid salt

Part A: 4-(4′-Chloro-1′-oxobutyl)pyridine (13A).

Prepared according to Sato et. al., Chem. Phar. Bull. 1978 26(1), 3296to produce 13A as a brown oil. ¹H NMR(300 MHz, CDCl₃, δ): 8.85-8.80 (m,2H), 7.80-7.75 (m, 2H), 3.69 (t, 2H, J 6 Hz), 3.20 (t, 2H, J=7 Hz),2.30-2.30 (m, 2H). IR(KBr, cm⁻¹): 1698 (s).

Part B: 2-((4-(4-Pyridyl)-4-oxobutyl))-1,2,3,4-tetra-hydroisoquinoline(13B).

1,2,3,4-Tetrahydroisoquinoline was alkylated with chloride 13Aanalogously to Example 6 to yield amine 13B (37% yield) as a solid afterflash chromatographic purification. ¹H NMR(300 MHz, CDCl₃, δ): 8.76-8.71(m, 2H), 7.73-7.68 (m, 2H), 7.15-6.95 (m, 4H), 3.56 (s, 2H), 3.05 (t,2H, J=7 Hz), 2.80 (t, 2H, J=6 Hz), 2.69 (t, 2H, J=6 Hz), 2.57 (t, 2H,J=7 Hz), 2.06 (pentet, 2H, J =7 Hz). ¹³C NMR(300 MHz, CDCl₃, δ): 199.43,150.77, 143.07, 134.67, 134.29, 128.86, 126.51, 126.10, 125.56, 121.00,57.09, 55.88, 50.84, 36.48, 28.92, 21.84. IR(KBr, cm⁻¹) : 1696 (s). UV(MeOH): λmax 273 nm, ε 3460; λmax 267 nm, ε 3090; MS(ESI) m/e 281 (base,M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 281.1654. Found: 281.1638.

Part C: 2-((4-(4-Pyridyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt (13).

Usual method from 13B. m.p. 108-109° C. Elemental analysis. Calc'd forC₂₂H₂₄NO₅: C, 66.65; H, 6.10; N,7.08. Found: C, 66.54; H, 6.07; N, 7.01.¹H NMR(300 MHz, CD₃OD, δ): 8.76-8.74 (m, 2H), 7.90-7.88 (m, 2H),7.30-7.19 (m, 4H), 6.21 (s, 2H), 4.88 (s, 2H), 4.46 (s, 2H), 3.61 (t,2H, J=7 Hz), 3.40-3.18 (m, 6H), 2.30-2.20 (m, 2H). ¹³C NMR(300 MHz,CDCl₃, δ): 200.32, 171.65, 152.34, 145.34, 137.49, 133.10, 130.75,130.31, 129.95, 129.13, 128.78, 123.65, 57.46, 55.27, 52.06, 37.31,27.31, 20.25. IR(KBr, cm⁻¹): 3600-2300 (m, br), 1698 (s). UV(MeOH): λmax272 nm, ε 2340. MS(CI, NH₃) m/e 281 (base, M+H⁺). HRMS(CI, NH₃) m/eCalc'd for (M+H⁺): 281.1654. Found: 281.1659.

Example 14

2-((4-(3-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline (1:1)maleic acid salt

Part A: 4-Chloro-3′-fluorobutyrophenone (14A)

Prepared according to Janssen, U.S. Pat. No. 2,973,365 (1961).

Part B:2-((4-(3-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline (14B)

1,2,3,4-Tetrahydroisoquinoline was alkylated with chloride 14A in theusual way to afford adduct 14B (58% yield) as an oil. ¹H NMR(300 MHz,CDCl₃, δ): 7.74-7.71 (m, 1H), 7.65-7.60 (m, 1H), 7.43-7.36 (m, 1H),7.25-7.19 (m, 1H), 7.15-7.08 (m, 3H), 7.00-6.98 (m, 1H), 3.61 (s, 2H),3.05 (t, 2H, J=7 Hz), 2.88 (t, 2H, J=6 Hz), 2.72 (t, 2H, J=7 Hz), 2.59(t, 2H, J=7 Hz), 2.05 (pentet, 2H, J=7 Hz). ¹³C NMR(300 MHz, CDCl₃, δ):198.84, 162.80 (d), 139.30, 134.60, 130.10, 128.62, 126.56, 126.09,125.57, 123.80, 119.80, 114.76, 57.31, 56.07, 50.87, 36.39, 29.11,21.78. IR(KBr, cm⁻¹): 1688 (s). UV(MeOH): λmax 283 nm, ε 2910; λmax 273nm, ε 2880; λmax 266 nm, ε 2430; λmax 238 nm, ε 16,300. MS(CI, NH₃) m/e298 (base, M +H⁺). HRMS(CI, NH₃) m/e Calc'd for M+H⁺): 298.1607. Found:298.1619.

Part C:2-((4-(3-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline (1:1)maleic acid salt (14)

Usual method from 14B. Recrystallized from benzene as a white solid.m.p. 139-140° C. Elemental analysis. Calc'd for C₂₃H₂₄FNO₅: C, 66.82; H,5.85; N, 3.40; F, 4.61. Found: C, 66.89; H, 5.75; N, 3.26; F, 4.69. HNMR(300 MHz, CD₃OD, δ): 7.83 (d, 1H, J=8 Hz), 7.71-7.66 (m, 1H),7.60-7.48 (m, 1H), 7.40-7.20 (m, 5H), 6.18 (m, 2H), 4.96 (br s, 2H),4.50 (s, 4H), 3.64 (t, 2H, J=6 Hz), 3.39-3.29 (m, 2H), 3.28-3.19 (m,4H), 2.29-2.19 (m, 2H). ¹³C NMR(300 MHz, CDCl₃, δ): 197.53, 169.37,162.80, 138.60, 135.18, 130.80, 130.40, 128.02, 127.75, 126.60, 123.80,119.80, 114.00, 55.31, 52.95, 49.74, 34.81, 24.98, 18.18. IR(KBr,cm⁻¹):3600-2300 (m, br), 1688 (s), UV(MeOH): λmax 283 nm, ε 2500; λmax272 nm, ε 2290; λmax 238 nm, ε 16,600. MS(GC/MS, H₂O) m/e 298 (base,M+H⁺).

Example 15

1,3-Dihydro-2-((4-(3-fluorophenyl)-4-oxobutyl)) isoindole (1:1) maleicacid salt (15)

Part A: 1,3-Dihydro-2-((4-(3-fluorophenyl)-4-oxobutyl)) isoindole (15A)

1,3-Dihydroisoindole hydrochloride was alkylated with chloride 14A instandard fashion. The product was purified by two successive flashchromatographies, eluting first with 2% MeOH in CHCl₃, then 33% EtOAc inhexane to provide 15A (10% yield) as a solid. ¹H NMR(300 MHz, CDCl₃, δ):7.76-7.72 (m, 2H), 7.66-7.60 (m, 1H), 7.45-7.37 (m, 1H), 7.26-7.19 (m,1H), 7.18 (s, 4H), 3.91 (s, 4H), 3.09 (t, 2H, J=7 Hz), 2.81 (t, 2H, J=7Hz), 2.08-1.98 (m, 2H). ¹³C NMR(300 MHz, CDCl₃, δ): 198.76, 140.05,130.16, 130.06, 126.65, 123.71, 122.20, 119.80, 114.70, 58.94, 55.09,36.26, 23.43. UV(MeOH): λmax 282 nm, ε 3080; λmax 272 nm, ε 3430; λmax266 nm, ε 3120; λmax 237 nm, ε 17,200. MS(GC/MS, H₂O) m/e 284 (base,M+H⁺).

Part B: 1,3-Dihydro-2-((4-(3-fluorophenyl)-4-oxobutyl)) isoindole (1:1)maleic acid salt (15)

Standard method from 15A. Recrystallized from benzene. m.p. 130-131° C.Elemental analysis. Calc'd for C₂₂H₂₂FNO₅: C, 66.16; H, 5.55; N, 3.52;F, 4.77. Found: C, 66.01; H, 5.50; N, 3.47; F, 4.80. H NMR(300 MHz,CD₃OD, δ): 7.85-7.82 (m, 1H), 7.72-7.68 (m, 1H), 7.57-7.49 (m, 1H),7.40-7.31 (m, 5H), 6.20 (s, 2H), 4.90 (br s, 2H), 4.76 (s, 4H),3.53-3.48 (m, 2H), 3.24 (t, 2H, J=7 Hz), 2.25-2.15 (m, 2H). ¹³C NMR(300MHz, CD₃OD, δ): 197.47, 169.36, 162.80, 138.60, 135.07, 133.60, 130.37,128.74, 123.79, 122.58, 119.80, 114.00, 58.42, 54.25, 34.70, 19.59.IR(KBr, cm⁻¹): 1694 (s), 1686 (s). UV(MeOH): λmax 283 nm, ε 1760; λmax271 nm, ε 1830; λmax 238 nm, ε 11,600. MS(GC/MS, H₂O) m/e 284 (base,M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M⁺): 283.1372. Found: 283.1373.

Example 16

2,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))-1H-benz[de]isoquinoline(1:1) maleic acid salt (16)

Part A: 2,3-Dihydro-1H-benz[de]isoquinoline (16A)

1,8-Naphthalimide (94% pure, 10 g, 48 mmol) and LiAlH₄ (10.4 g, 270mmol) were stirred in dry THF (500 mL) at RT under N₂ for 4 days. Aftercareful quenching with Na₂SO₄·10H₂O, filtration, and concentration invacuo, the residue was extracted with EtOAc and H₂O, then brine, dried(MgSO₄), and concentrated. The crude product was purified by flashchromatography on silica gel 60, eluting with 3% to 15% MeOH in CHCl₃ toprovide the amine 16A (1.05 g) as a dark solid. ¹H NMR(300 MHz, CDCl₃,δ): 7.68 (d, 2H, J=8 Hz), 7.38 (dd, 2H, J=8, 7 Hz), 7.15 (d, 2H, J 7Hz), 4.29 (s, 4H), 2.60-2.40 (br s, 1H). MS(CI, NH₃) m/e 170 (base,M+H⁺)

Part B:2,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))-1H-benz[de]isoquinoline(16B)

Amine 16A (1.0 g, 5.9 mmol) was alkylated with4-chloro-4′-fluorobutyrophenone (1.19 g, 5.9 mmol) in the usual way. Thecrude product was purified by flash chromatography on silica gel 60,eluting with 2% MeOH in CHCl₃ to provide amine adduct 16B as a brownoil. ¹H NMR(300 MHz, CDCl₃, δ): 8.95-8.80 (m, 2H), 7.65 (d, 2H, J=8 Hz),7.36 (t, 2H, J=7 Hz), 7.15 (d, 2H, 7 Hz), 6.91 (t, 2H, J=9 Hz), 3.91 (s,4H), 2.99 (t, 2H, J=7 Hz), 2.67 (t, 2H, J=7 Hz), 2.15-2.00 (m, 2H).IR(KBr, cm⁻¹): 1684 (s). UV(MeOH): λmax 242 nm, ε 27,700; λmax 227 nm, ε22,700. MS(CI, NH₃) m/e 334 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd forM+H⁺): 334.1607. Found: 334.1595.

Part C:2,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))-1H-benz[de]isoquinoline(1:1) maleic acid salt (16)

Standard method from 16B. Yield yellow solid 16. m.p. 151-155° C.Elemental analysis. Calc'd for C₂₆H₂₄FNO₅: C, 69.48; H, 5.38; N, 3.13;F, 4.24. Found: C, 69.21; H, 5.40; N, 3.02; F, 4.47. ¹H NMR (300 MHz,CD₃OD, δ): 8.10-8.00 (m, 2H), 7.90-7.85 (m, 2H), 7.60-7.40 (m, 4H), 7.19(t, 2H, J=9 Hz), 6.20 (s, 2H), 4.72 (s, 4H), 3.45-3.30 (m, 2H), 3.22 (t,2H, J=7 Hz), 2.35-2.20 (m, 2H). ¹³C NMR(300 MHz, CD₃OD, δ): 197.33,169.35, 166.00, 135.18, 132.91, 130.58, 127.94, 126.06, 125.95, 123.83,115.20, 55.17, 54.40, 34.61, 18.62. IR(KBr, cm⁻¹): 3600-2400 (m, br),1684 (s). UV (MeOH): λmax 316 nm, ε 700; λmax 285 nm, ε 5,700; λmax 275nm, ε 5400; λmax 226 nm, ε 57,000. MS(CI, NH₃) m/e 334 (base, M+H⁺).HRMS(EI) m/e Calc'd for (M⁺) 333.1529. Found: 333.1554.

Example 17

2-((4-Oxo-4-(2-thienyl)butyl))-1,2,3,4-tetrahydroisoquinoline (1:1)maleic acid salt

Part A: 2-((4-Oxo-4-(2-thienyl)butyl))-1,2,3,4-tetrahydroisoquinoline(17A)

Prepared in standard fashion from commercially available4-chloro-2′-butyrothienone and 1,2,3,4-tetrahydroisoquinoline. Purifiedby flash chromatography, eluting with 1:1 EtOAc/hexane to provide 17A(58% yield) as a yellow oil. ¹H NMR(300 MHz, CDCl₃, δ): 7.72-7.70 (m,1H), 7.60-7.58 (m, 1H), 7.15-6.98 (m, 5H), 3.62 (s, 2H), 3.01 (t, 2H,J=7 Hz), 2.87 (t, 2H, J=6 Hz), 2.72 (t, 2H, J=6 Hz), 2.59 (t, 2H, J=7Hz), 2.10-2.00 (m, 2H). ¹³C NMR(300 MHz, CDCl₃, δ): 193.10, 144.56,134.92, 134.43, 133.34, 131.79, 128.64, 128.05, 126.59, 126.08, 125.58,57.37, 56.10, 50.83, 37.01, 29.19, 22.14. . IR(KBr, cm⁻¹): 1662 (s). UV(MeOH): max 282 nm, ε 260. MS(CI, NH₃) m/e 286 (base, M+H ). HRMS(CI,NH₃) m/e Calc'd for (M+H⁺): 286.1266. Found: 286.1259.

Part B: 2-((4-Oxo-4-(2-thienyl)butyl))-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt (17)

Standard method from 17A to provide solid 17. m.p. 154-155° C. Elementalanalysis. Calc'd for C₂₁H₂₃NO₅S: C, 62.82; H, 5.77; N, 3.50; S, 8.00.Found: C, 62.58; H, 5.67; N, 3.41; S, 7.86. H NMR(300 MHz, DMSO-d₆, δ):8.01 (d, 1H, J=5 Hz), 7.98-7.96 (m, 1H), 7.35-7.20 (m, 6H), 6.03 (s,2H), 4.50-4.30 (br s, 2H), 3.60-3.00 (m, 10H), 2.15-2.00 (m, 2H).IR(KBr, cm⁻¹): 3600-2400 (m, br), 1666 (s). MS(CI, NH₃) m/e 286 (base,M+H⁺). HRMS(CI, NH₃) m/e Calc'd for M+H⁺): 286.1266. Found: 286.1206.

Example 18

6,7-Dimethoxy-2-((4-(4-fluorophenyl)oxobutyl))-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt

Part A: 6,7-Dimethoxy-2-((4-(4-fluorophenyl)oxobutyl))-1,2,3,4-tetrahydroisoquinoline (18A)

Commercially available 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride was alkylated in standard fashion to provide amine 18A(54% yield) as a brown oil. ¹H NMR(300 MHz, CDCl₃, δ): 8.01-7.95 (m,2H), 7.10 (t, 2H, J=9 Hz), 6.59 (s, 1H), 6.51 (s, 1H), 3.84 (s, 6H),3.54 (s, 2H), 3.05 (t, 2H, J=7 Hz), 2.81-2.77 (m, 2H), 2.72-2.70 (m,2H), 2.58 (t, 2H, J=7 Hz), 2.08-1.99 (m, 2H). IR(KBr, cm⁻¹) : 1684 (s).MS(CI, NH₃) m/e 358 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺):358.1818. Found: 358.1828.

Part B:6,7-Dimethoxy-2-((4-(4-fluorophenyl)oxobutyl))-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt (18)

Standard method from 18A. Yield colorless solid 18. m.p. 144-146° C.Elemental analysis, sample dried by analyst. Calc'd for C₂₅H₂₈FNO₇: C,63.42; H, 5.96; N, 2.97; F, 4.01. Found: C, 63.59; H, 5.92; N, 2.73; F,4.07. ¹H NMR(300 MHz, DMSO-d₆, δ): 8.06 (dd, 2H, J=7, 6 Hz), 7.39 (t,2H, J=9 Hz), 6.84 (s, 1H), 6.82 (s, 1H), 6.03 (s, 2H), 4.40-4.20 (br s,2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.70-3.15 (m, 8H), 3.10-2.95 (br s,2H), 2.20-2.00 (m, 2H). IR(KBr, cm⁻¹): 3600-2400 (m, br), 1686 (s, br).UV(MeOH): λmax 281 nm, ε 6700; λmax 236 nm, ε 23,100. MS(CI, NH₃) m/e358 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 358.1818. Found:358.1829.

Example 19

(+/−)-trans-2-((4-(4-Fluorophenyl)oxobutyl))-perhydroisoquinoline (1:1)maleic acid salt

Part A:(+/−)-trans-2-((4-(4-Fluorophenyl)oxobutyl))-perhydroisoquinoline (19A)

Commercially available (+/−)-trans-perhydroisoquinoline was alkylated inthe usual way, then purified by flash chromatography on silica gel 60,eluting with 1:1 EtOAc/hexane to provide 19A (65% yield) as a brown oil.¹H NMR(300 MHz, CDCl₃, δ): 8.05-7.95 (m, 2H), 7.12 (t, 2H, J=9 Hz), 2.96(t, 2H, J=7 Hz), 2.93-2.85 (m, 1H), 2.76-2.72 (m, 1H), 2.36 (t, 2H, J=7Hz), 2.00-1.90 (m, 3H), 1.80-1.45 (m, 6H), 1.38-1.05 (m, 4H), 1.00-0.80(m, 3H). IR(KBr, cm⁻¹): 1686 (s). UV(MeOH): λmax 337 nm, ε 1700; λmax243 nm, ε 10,900.

Part B:(+/−)-trans-2-((4-(4-Fluorophenyl)oxobutyl))-perhydroisoquinoline (1:1)maleic acid salt (19)

Standard method from 19A. Yield colorless solid 19. m.p. 157-158° C.Elemental analysis. Calc'd for C₂₃H₃₀FNO₅: C, 65.85; H, 7.22; N, 3.35;F, 4.54. Found: C, 65.66; H, 7.17; N, 3.23; F, 4.55. ¹H NMR(300 MHz,DMSO-d₆, δ): 8.12-8.04 (m, 2H), 7.39 (t, 2H, J=9 Hz), 6.02 (s, 2H),3.52-3.48 (m, 1H), 3.37-3.30 (m, 2H), 3.16 (t, 2H, J=7 Hz), 3.14-3.00(m, 2H), 3.00-2.90 (m, 1H), 2.70-2.60 (m, 1H), 2.04-1.95 (m, 5H),1.45-1.05 (m, 5 H), 1.00-0.85 (m, 2H). MS(CI, NH₃) m/e 304 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for M+H⁺): 304.2077. Found: 304.2091.

Example 20

2-((3-(1,3-Dihydro-2H-benzimidazol-2-one)-1-ylpropyl))-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt

Part A:2-((3-(1,3-Dihydro-2H-benzimidazol-2-one)-1-ylpropyl))-1,2,3,4-tetrahydroisoquinoline(20A)

1,2,3,4-Tetrahydroisoquinoline was alkylated with commercially available1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazole-2-one in typical fashionto provide solid 20A (90% yield) after flash chromatography, elutingwith 8% MeOH in CHCl₃. m.p. 141-143° C. ¹H NMR(300 MHz, CDCl₃, δ):7.20-7.00 (m, 9H), 4.01 (t, 2H, J=7 Hz), 3.62 (s, 2H), 2.91 (t, 2H, J=6Hz), 2.71 (t, 2H, J=6 Hz), 2.58 (t, 2H, J=7 Hz), 2.08 (pentet, 2H, J=7Hz). ¹³C NMR(300 MHz, CDCl₃, δ): 156.03, 134.78, 134.35, 130.58, 128.66,128.20, 126.59, 126.15, 125.63, 121.36, 121.09, 109.71, 108.04, 56.08,55.05, 50.94, 38.87, 29.19, 26.06. IR(KBr, cm⁻¹): 1716 (s), 1664 (m).MS(CI, NH₃) m/e 308 (base, M+H ). HRMS(CI, NH₃) m/e Calc'd for M+H⁺):308.1763. Found: 308.1774.

Part B:2-((3-(1,3-Dihydro-2H-benzimidazol-2-one)-1-ylpropyl))-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt (20)

Standard method from 20A to yield a solid 20. m.p. 153-154° C. Elementalanalysis. Calc'd for C₂₃H₂₅FN₃O₅: C, 65.24; H, 5.95; N, 9.92. Found: C,64.97; H, 5.89; N, 9.90. ¹H NMR(300 MHz, DMSO-d₆, δ): 7.30-7.15 (m, 6H),7.10-7.00 (m, 4H), 6.03 (s, 2H), 3.92 (t, 2H, J=7 Hz), 3.60-3.00 (m,10H), 2.20-2.05 (m, 2H). UV(MeOH): λmax 281 nm, ε 6400. MS(CI, NH₃) m/e308 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 308.1763. Found:308.1762.

Example 21

2-(3-Phenylisoxazol-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline (1:1)maleic acid salt

Part A: 2-(3-Phenylisoxazol-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline(21A)

Prepared from 1,2,3,4-tetrahydroisoquinoline and5-(bromomethyl)-3-phenylisoxazole under typical conditions. Purificationby flash chromatography on silica gel 60, eluting with 25% EtOAc inhexane produced adduct 21A (81% yield). ¹H NMR(300 MHz, CDCl₃, δ):7.83-7.80 (m, 2H), 7.48-7.40 (m, 3H), 7.16-7.11 (m, 3H), 7.08-6.99 (m,1H), 6.57 (s, 1H), 3.91 (s, 2H), 3.76 (s, 2H), 3.00-2.80 (m, 4H). ¹³CNMR(300 MHz, CDCl₃, δ): 170.25, 162.45, 134.04, 133.75, 129.97, 129.12,128.92, 128.72, 126.81, 126.56, 126.36, 125.78, 101.26, 85.61, 53.20,50.75, 29.03. MS(CI, NH₃) m/e 291 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'dfor (M+H⁺): 291.1497. Found: 291.1512.

Part B: 2-(3-Phenylisoxazol-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt (21)

Standard method. Recrystallized from isopropanol. m.p. 190-192° C.UV(MeOH): λmax 240 nm, ε 13,900. MS(CI, NH₃) m/e 308 (base, M+H++NH₃),291 (98%, M+H⁺). HRMS(EI) m/e Calc'd for (M+): 290.1419. Found:290.1402.

Example 22

(+/−)-2-((3-(4-Fluorophenyl)-2-isoxazolin-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt

Part A: (+/−)-5-(Chloromethyl)-3-(4-fluorophenyl)-2-isoxazoline (22A).

Chlorox bleach (200 mL, ca. 140 mmol) was added dropwise over 20 min toa 0° C. solution of allyl chloride (5.7 mL, 70 mmol) andsyn-4-fluorobenzaldoxime (10 g, 70 mmol) in CH₂Cl₂ (350 mL). After 15min more, phases were separated. The aqueous layer was extracted withmore CH₂Cl₂ (400 mL). The combined organic phases were extracted withH₂O (100 mL), dried (Na₂SO₄), filtered, and concentrated. The crudeproduct was purified by flash chromatography, eluting with a gradient ofhexane to 25% EtOAc in hexane to yield 22A (4.5 g) as a yellow solidafter concentration. m.p. 60-62° C. ¹H NMR(300 MHz, CDCl₃, δ): 7.71-7.64(m, 2H), 7.15-7.07 (m, 2H), 5.05-4.96 (m, 1H), 3.71 (dd, 1H, J=11, 4Hz), 3.59 (dd, 1H, J =11, 7 Hz), 3.50 (dd, 1H, J=17, 10 Hz), 3.34 (dd,1H, J =17, 6 Hz). ¹³C NMR(300 MHz, CDCl₃, δ): 163.85 (d, J=250 Hz),155.19, 128.73 (d, J=9 Hz), 125.37, 115.89 (d, J=22 Hz), 79.89, 44.89,38.55. IR(KBr, cm⁻¹): 1604 (m-s), 1514 (s), 1232 (m-s), 838 (s).UV(MeOH): λmax 259 nm, ε 15,0000. MS(H₂O-GC/MS) m/e 214 (base, M+H⁺, 1Cl isotope pattern). HRMS(EI) m/e Calc'd for (M⁺): 213.0357. Found:213.0355.

Part B:(+/−)-2-((3-(4-Fluorophenyl)-2-isoxazolin-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline(22B).

1,2,3,4-Tetrahydroisoquinoline was alkylated with chloride 22A in theusual way. The crude product was purified by flash chromatography onsilica gel 60, eluting with 33% EtOAc in hexane to provide, aftersolvent evaporation, amine 22B (55% yield) as a yellow solid. ¹H NMR(300MHz, CDCl₃, δ): 7.69-7.62 (m, 2H), 7.16-7.01 (m, 6H), 5.07-4.97 (m, 1H),3.79-3.26 (m, 4H), 2.96-2.74 (m, 6H). ¹³C NMR(300 MHz, CDCl₃, δ): 163.72(d, J=250 Hz), 155.64, 152.03, 150.32, 143.33, 134.34 (d, J=34 Hz),128.70, 128.62, 126.41 (d, J=17 Hz), 125.71, 115.90 (d, J=22 Hz), 80.01,61.22, 56.62, 51.63, 39.01, 29.01. IR(KBr, cm⁻¹): 1604 (s). UV(MeOH):λmax 319 nm, ε 930; λmax 261 nm, ε 16,900. MS(CI, NH₃) m/e 311 (base,M+H⁺). HRMS(CI, NH₃) m/e Calc'd for M+H⁺): 311.1560. Found: 311.1557.

Part C:(+/−)-2-((3-(4-Fluorophenyl)-2-isoxazolin-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline(1:1) maleic acid salt (22)

Standard procedure. Recrystallized from isopropanol. m.p. 153-155° C. ¹HNMR(300 MHz, CD₃OD, δ): 7.80-7.70 (m, 2H), 7.33-7.14 (m, 6H), 6.21 (s,2H), 5.40-5.25 (m, 1H), 4.88 (br s, 2H), 4.53 (s, 2H), 3.80-3.65 (m,3H), 3.60-3.45 (m, 2H), 3.30-3.20 (m, 3H). MS(CI, NH₃) m/e 311 (base,M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 311.1560. Found: 311.1540.

Example 23

1,3-Dihydro-2-((3-(4-fluorophenoxy)propyl)) isoindole (1:1) maleic acidsalt.

Part A: N-((3-(4-Fluorophenoxy)propyl))phthalimide (23A)

4-Fluorophenol (5.0 g, 45 mmol), N-(3-bromopropyl) phthalimide (12 g, 45mmol), and K₂CO₃ (6.2 g, 45 mmol) were stirred in DMF (30 mL) for 14h atRT under N₂. The mixture was then diluted with EtOAc, stirred withMgSO₄, filtered, and concentrated in vacuo. The product was purified byflash chromatography on silica gel 60, eluting with 20% EtOAc in hexaneto yield, after solvent evaporation, imide 23A (10.7 g) as a colorlesssolid. m.p. 110-112° C. ¹H NMR(300 MHz, CDCl₃, d): 7.88-7.82 (m, 2H),7.78-7.69 (m, 2H), 6.96-6.88 (m, 2H), 6.78-6.71 (m, 2H), 3.99 (t, 2H,J=6 Hz), 3.91 (t, 2H, J=7 Hz), 2.17 (pentet, 2H, J=7 Hz). ¹³C NMR(300MHz, CDCl₃, d): 168.33, 157.20, 154.79, 133.92, 132.13, 123.21, 115.60,115.41, 66.30, 35.42, 28.32. UV(MeOH): lmax 286 nm, e 3900; lmax 280 nm,e 4200; lmax 241 nm, e 12,300; lmax 219 nm, e 51,000. MS(CI, NH₃) m/e317 (base, M+H⁺NH₃), 300 (63%, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for(M+H⁺): 300.1036. Found: 300.1039.

Part B: 1,3-Dihydro-2-((3-(4-fluorophenoxy)propyl)) isoindole (23B)

Imide 23A (5.0 g, 17 mmol) was reduced with LiAlH₄ (3.3 g, 86 mmol) indry THF (400 mL) at reflux under N₂ overnight. After careful quenchingwith Na₂SO₄·10H₂O, the mixture was filtered through Celite, rinsed withmore THF, and concentrated. The product was purified by flashchromatography on silica gel 60, eluting with a gradient of 20% to 50%EtOAc in hexane to yield, after solvent evaporation, amine 23B (3.1 g).¹H NMR(300 MHz, CDCl₃, d): 7.20 (s, 4H), 7.00-6.80 (m, 4H), 4.05 (t, 2H,J=7 Hz), 3.95 (s, 4H), 2.91 (t, 2H, J=7 Hz), 2.15-2.00 (m, 2H). ¹³CNMR(300 MHz, CDCl₃, d): 157.30, 155.19, 140.07, 126.72, 122.26, 115.60,115.57, 66.74, 59.18, 52.67, 28.83. IR(KBr, cm⁻¹): 1206 (s). UV(MeOH):lmax 280 nm, e 2700; lmax 272 nm, e 2900. MS(CI, CH₄) m/e 272 (base,M+H^(+).)

Part C: 1,3-Dihydro-2-((3-(4-fluorophenoxy)propyl)) isoindole (1:1)maleic acid salt (23)

Standard procedure. m.p. 115-117° C. Elemental analysis. Calc'd forC₂₁H₂₂FNO₅: C, 65.11; H, 5.72; N, 3.63; F, 4.90. Found: C, 65.06; H,5.60; N, 3.53; F, 5.00. 1¹H NMR(300 MHz, DMSO-d₆, d): 7.43-7.35 (m, 4H),7.20-7.10 (m, 2H), 7.00-6.95 (m, 2H), 6.03 (s, 2H), 4.07 (t, 2H, J=6Hz), 3.49 (t, 2H, J=7 Hz), 3.40-3.30 (br s, 1H), 2.20-2.09 (m, 2H). ¹³CNMR(300 MHz, DMSO-d₆, d): 167.78, 157.10, 155.00, 136.11, 135.05,128.85, 123.34, 116.31, 116.20, 65.72, 58.47, 51.98, 25.82. IR(KBr,cm⁻¹): 2800-2350 (m, br), 1576 (s), 1206 (s). UV(MeOH): lmax 279 nm, e2300; lmax 271 nm, e 2400. MS(CI, NH₃) m/e 272 (base, M+H⁺). HRMS(CI,NH₃) m/e Calc'd for (M+H⁺): 272.1451. Found: 272.1443.

Example 24

2-((3-(4-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline (1:1)hydrochloride salt.

4-Fluorothiophenol (6.2 g, 48 mmol), 1-bromo-3-chloropropane (4.7 mL, 48mmol), and powdered K₂CO₃ (3.5 g, 25 mmol) were stirred in DMF (25 mL)from 0° C. to RT overnight. The next morning, a small reaction aliquotwas removed and extracted with EtOAc and 1 M HCl; the organic phase wasevaporated and dried under vacuum, then analyzed by ¹H NMR. The NMRspectrum indicated near quantitative conversion to1-(4-fluorophenylthio)-3-chloropropane. ¹H NMR(300 MHz, CDCl₃, δ):7.40-7.33 (m, 2H), 7.05-6.97 (m, 2H), 3.65 (t, 2H, J=6 Hz), 3.02 (t, 2H,J=7 Hz), 2.03 (pentet, 2H, J=7 Hz).

Diisopropylethylamine (8.3 mL, 48 mmol), 1,2,3,4-tetrahydroisoquinoline(6.0 mL, 48 mmol), and NaI (0.75 g, 5 mmol) were added to the abovereaction mixture containing the just made chlorosulfide. The resultingmixture was then heated to ca. 70° C. for 18 h, then to 90° C. for 4 h.After cooling, the mixture was extracted with EtOAc (1L) and 0.5 M NaOH(200 mL), then H₂O(5×250 mL), finally brine (50 mL). The solution wasdried (Na₂SO₄), filtered, and concentrated to yield crude amine2-((3-(4-fluoro-phenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline. Thiscrude amine product was immediately converted to the salt by dilutingwith CH₂Cl₂ (50 mL) and adding 1 M HCl (75 mL). Diethyl ether was added,and the resulting salt precipitate was collected by filtration.Recrystallization from isopropanol produced salt 24 (9.3 g, 57% overall)of excellent purity. m.p. 171-173° C. Elemental analysis. Calc'd forC₁₈H₂₁ClFNS: C, 63.98; H, 6.26; N, 4.16; F, 5.62; Cl, 10.49; S, 9.49.Found: C, 63.70; H, 6.36; N, 4.13; F, 5.71; Cl, 10.22; S, 9.50. ¹HNMR(300 MHz, CD₃OD, δ): 7.50-7.43 (m, 2H), 7.32-7.16 (m, 4H), 7.12-7.04(m, 2H), 4.88 (br s, 1H), 4.43 (br s, 2H), 3.57 (br s, 2H), 3.43-3.38(m, 2H), 3.17 (t, 2H, J=6 Hz), 3.03 (t, 2H, J=7 Hz), 2.16-2.06 (m, 2H).¹³C NMR(300 MHz, CD₃OD, δ): 162.09 (d, J=246 Hz), 132.72 (d, J=8 Hz),130.63, 130.24, 128.42, 128.06, 127.32, 126.86, 126.43, 115.77, 54.64,52.86, 49.86, 31.20, 24.89, 23.53. IR(KBr, cm⁻¹): 2724-2418 (s, br),1490 (s), 1222 (s), 822 (s), 756 (s). UV(MeOH): λmax 252 nm, ε 6600.MS(CI, NH₃) m/e 302 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺):302.1379. Found: 302.1383.

Example 25

1,3-Dihydro-2-((3-(4-fluorophenylthio) propyl))isoindole (1:1)hydrochloride salt

Part A: N-((3-(4-Fluorophenylthio)propyl)phthalimide (25A)

4-Fluorothiophenol (6.0 mL, 56 mmol), N-(3-bromopropyl)phthalimide (15g, 56 mmol), and powdered K₂CO₃ (7.7 g, 56 mmol) were stirred in DMF (50mL) at RT under N₂ for 29 h. Solvent was removed in vacuo, and theresidue was extracted with EtOAc (1L) and H₂O (5×200 mL), then brine (50mL). The solution was dried (Na₂SO₄), filtered, and concentrated toyield sulfide imide 25A in quantitative yield as a crystalline solid.m.p. 73-75° C. Elemental analysis. Calc'd for C₁₇H₁₄FNO₂S: C, 64.75; H,4.47; N, 4.44; F, 6.02; S, 10.17. Found: C, 64.73; H, 4.42; N, 4.37; F,6.16; S, 9.90. H NMR(300 MHz, CDCl₃, δ): 7.88-7.81 (m, 2H), 7.75-7.69(m, 2H), 7.41-7.34 (m, 2H), 7.02-6.94 (m, 2H), 3.81 (t, 2H, J=7 Hz),2.88 (t, 2H, J=7 Hz), 1.95 (pentet, 2H, J=7 Hz). ¹³C NMR(300 MHz, CDCl₃,δ): 168.23, 161.95 (d, J=247 Hz), 133.95, 133.11 (d, J=8 Hz), 132.03,130.54, 123.20, 116.02, 36.86, 32.77, 28.07. IR(KBr, cm⁻¹): 1772 (w),1712 (s). UV(MeOH): λmax 219 nm, ε 78,000. MS(CI, NH₃) m/e 333 (base,M+NH₄ ⁺), 316 (45%, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for M+H⁺): 316.0808.Found: 316.0795.

Part B: 1,3-Dihydro-2-((3-(4-fluorophenylthio)propyl)) isoindole (25B)

Sulfide imide 25A (7.9 g, 25 mmol) was reduced with BH₃·THF (0.7 M inTHF, 100 mL, 70 mmol) in dry THF (25 mL) under N₂ at RT for 2 days, thenat reflux for 2 days. After cooling, the excess borane was quenched byslow addition of MeOH (50 mL), then boiling for 1 h. After cooling andconcentration in vacuo, 0.1 M HCl (200 mL) was added; the resultingmixture was stirred for 75 min at RT. The solution was basified byadding 1 M NaOH (50 mL) and extracted with EtOAc (500 mL) plus brine(100 mL) to speed phase separation. The organic phase was then extractedwith half-saturated brine (100 mL), dried (Na₂SO₄), filtered, andconcentrated. Flash chromatographic purification on silica gel 60,eluting with hexane to 4:1 EtOAc/hexane provided, after solventevaporation, amine 25B (4.04 g) as a tan solid. m.p. 58-63° C. Elementalanalysis. Calc'd for C₁₇H₁₈FNS: C, 71.05; H, 6.31; N, 4.87; F, 6.61; S,11.16. Found: C, 70.93; H, 6.25; N, 4.85; F, 6.68; S, 10.95. ¹H NMR(300MHz, CDCl₃, δ): 7.37-7.31 (m, 2H), 7.17 (s, 4H), 7.01-6.93 (m, 2H), 3.80(s, 4H), 2.98 (t, 2H, J=7 Hz), 2.81 (t, 2H, J=7 Hz), 1.86 (pentet, 2H,J=7 Hz). ¹³C NMR(300 MHz, CDCl₃, δ): 161.71 (d, J=246 Hz), 140.02,132.21 (d, J=8 Hz), 131.47, 126.74, 122.27, 115.99, (d, J=22 Hz), 59.08,54.61, 32.78, 28.52. IR(KBr, cm⁻¹): 1590 (w), 1490 (s), 1220 (m), 824(m), 746 (m). UV(MeOH): λmax 253 nm, ε 6900. MS(CI, NH₃) m/e 288 (base,M+H⁺). HRMS(CI, NH₃) m/e Calc'd for M+H⁺): 288.1222. Found: 288.1216.

Part C: 1,3-Dihydro-2-((3-(4-fluorophenylthio)propyl)) isoindole (1:1)hydrochloride salt (25)

The crude solid salt was prepared as described for Example 24. The saltwas purified by boiling in benzene, decanting after slight cooling froma small amount of dark oily ppt. After cooling further and standing atRT, 25 (81% yield) was collected as off-white flakes. m.p. 125-126°.Elemental analysis. Calc'd for C₁₇H₁₉ClFNS: C, 63.05; H, 5.91; N, 4.32;Cl, 10.95; F, 5.88; S, 9.90. Found: C, 63.09; H, 5.85; N, 4.25; Cl,11.05; F, 6.05; S, 9.66. ¹H NMR(300 MHz, DMSO-d₆, δ): 12.43 (br s, 1H),7.52-7.45 (m, 2H), 7.40-7.33 (m, 4H), 7.25-7.17 (m, 2H), 4.72 (br s,2H), 4.49 (br s, 2H), 3.49-3.44 (m, 2H), 3.09 (t, 2H, J=7 Hz), 2.05(pentet, 2H, J=7 Hz). ¹³C NMR(300 MHz, DMSO-d₆, δ): 161.43 (d, J=244Hz), 134.81, 132.04 (d, J=8 Hz), 131.12, 128.75, 123.17, 116.52 (d, J=23Hz), 57.90, 53.19, 30.91, 25.04. IR(KBr, cm ⁻¹): 2632 (s), 2540 (m),2382 (m), 1588 (m), 1490 (s), 1218 (m), 828 (m), 750 (m). UV(MeOH): λmax252 nm, ε 6600. MS(CI, NH₃) m/e 288 (base, M+H⁺). HRMS(CI, NH₃) m/eCalc'd for M+H⁺): 288.1222. Found: 288.1220.

Example 26

1,3-Dihydro-2-((3-(4-fluorophenylsulfonyl) propyl))isoindole (1:1)maleic acid salt.

Part A: 1,3-Dihydro-2-((3-(4-fluorophenylsulfonyl) propyl))isoindole(26A).

Sulfide amine·hydrochloride 25 (2.0 g, 6.2 mmol) was stirred with Oxone(2KHSo₅·KHSO₄·K₂SO₄, 7.62 g, 12.4 mmol) in MeOH at RT overnight. Afterconcentration in vacuo the mixture was extracted with EtOAc (200 mL) and1 M NaOH (100 mL), then H₂O (100 mL), finally brine (25 mL). Thesolution was dried (Na₂SO₄), filtered, and evaporated to yield thesulfone amine free base 26A (2.1 g). MS(ESI) m/e 320 (base, M+H⁺).

Part B:1,3-Dihydro-2-((3-(4-fluorophenylsulfonyl) propyl))isoindole(1:1) maleic acid salt (26).

Standard method from crude 26A. Recrystallized from hot benzene/EtOH(2:1) to yield 26 as pale grey needles. m.p. 151-2° C. Elementalanalysis. Calc'd for C₂₁H₂₂FNO₆S: C, 57.92; H, 5.09; N, 3.23; F, 4.36;S, 7.36. Found: C, 57.89; H, 4.96; N, 3.10; F, 4.48; S, 7.14. ¹H NMR(300MHz, DMSO-d₆, δ): 8.05-8.00 (m, 2H), 7.56 (t, 2H, J=9 Hz), 7.42-7.35 (m,4H), 6.08 (s, 2H), 4.61 (br s, 4H), 3.52 (br t, 2H, J=8 Hz), 3.43 (br t,2H, J=8 Hz), 2.07-1.97 (br pentet, 2H, J=9 Hz). ¹³C NMR(300 MHz,DMSO-d₆, δ): 167.73, 165.64 (d, J=253 Hz), 135.84, 135.34, 135.18,131.52 (d, J=10 Hz), 128.76, 123.19, 117.24, 58.39, 52.66, 52.26, 19.97.IR(KBr, cm⁻¹): 2800-2350 (m, br), 1702 (w), 1620 (m), 1588 (s), 1492(s). UV(MeOH): λmax 270 nm, ε 920; λmax 263 nm, ε 1200;λmax 257 nm, ε1300. MS(CI, NH₃) m/e 320 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd forM+H⁺): 320.1121. Found: 320.1136.

Example 27

2-((3-(4-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline(1:1) hydrochloride salt.

Sulfide 24 was treated with Oxone as in Example 26, Part A to providethe free base sulfone 27A (quantitative) as an orange-brown oil. Thecrude product was immediately converted to its hydrochloride salt instandard fashion. The salt was recrystallized from boiling isopropanol(4×) to upgrade to the desired purity. Yield 27 (34% overall) as acolorless solid. m.p. 212-215° C. ¹H NMR(300 MHz, DMSO-d₆, δ): 10.90 (brs, 1H), 8.05-7.99 (m, 2H), 7.58-7.52 (m, 2H), 7.28-7.19 (m, 4H),4.53-4.22 (m, 2H), 3.63-2.96 (m, 8H), 2.16-2.11 (m, 2H). ¹³C NMR(300MHz, DMSO-d₆, δ): 165.61 (d, J=253 Hz), 135.48, 131.77, 131.52 (d, J=10Hz), 128.91, 128.78, 128.02, 127.05, 117.23 (d, J=23 Hz), 53.61, 52.43,52.06, 49.07, 25.14, 17.90. IR(KBr, cm⁻¹): 2900-2300 (s, br), 1588 (m),1494 (s), 1144 (s). UV(MeOH): λmax 258 nm, ε 590; λmax 252 nm, ε 520.MS(ESI) m/e 334 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺):334.1277. Found: 334.1282.

Example 28

2-((3-(3-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline (1:1)hydrochloride salt.

Prepared from 3-fluorothiophenol in analogous fashion to Example 24. Thehydrochloride salt was recrystallized from isopropanol to yield a palepink solid 28 (57% overall). m.p. 158-160° C. Elemental analysis. Calc'dfor C₁₉H₂₁ClFNS: C, 63.98; H, 6.26; Cl, 10.49; N, 4.16; F, 5.62; S,9.49. Found: C, 63.67; H, 6.38; Cl, 10.35; N, 4.03; F, 5.51; S, 9.77. ¹HNMR(300 MHz, DMSO-d₆, δ): 11.06 (br s, 1H), 7.41-7.00 (m, 8H), 4.53-4.48(m, 1H), 4.30-4.22 (m, 1H), 3.72-3.60 (m, 1H), 3.34-2.96 (m, 7H), 2.14(pentet, 2H, J=8 Hz). ¹³C NMR(300 MHz, DMSO-d₆, δ): 162.88 (d, J=246Hz), 139.05 (d, J=7 Hz), 131.93, 131.24 (d, J=8 Hz), 128.92 (d, J=4 Hz),127.89, 126.95, 124.15, 114.62 (d, J=23 Hz), 112.89 (d, J=21 Hz), 54.33,51.87, 48.94, 29.41, 25.16, 23.41. IR(KBr, cm⁻¹) : 2800-2400 (m-s, br),1598 (m-s), 1576 (m-s), 1472 (s). UV(MeOH): λmax 253 nm, ε 9650. MS(ESI)m/e 302 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for (M+H⁺): 302.1379.Found: 302.1379.

Example 29

2-((3-(3-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline(1:1) hydrochloride salt.

Prepared from sulfide hydrochloride 28 as in Example 27 to yield 29 (45%overall) as an off-white solid after recrystallization (isopropanol).m.p. 171-173° C. Elemental analysis. Calc'd for C₁₉H₂₁ClFNO₂S: C, 58.45;H, 5.72; Cl, 9.58; N, 3.80; F, 5.15; S, 8.68. Found: C, 58.18; H, 5.82;Cl, 9.30; N, 3.71; F, 4.97; S, 8.63. ¹H NMR(300 MHz, DMSO-d₆, δ): 11.01(br s, 1H), 7.82-7.64 (m, 4H), 7.30-7.18 (m, 4H), 4.53-4.48 (m, 1H),4.30-4.22 (m, 1H), 3.70-3.57 (m, 3H), 3.27-3.15 (m, 4H), 3.06-2.85 (m,1H), 2.18-2.10 (m, 2H). ¹³C NMR(300 MHz, DMSO-d₆, δ): 162.26 (d, J=249Hz), 141.15 (d, J=6 Hz), 132.43 (d, J=7 Hz), 131.86, 128.88, 128.83,127.91, 126.96, 124.53, 121.73 (d, J=21 Hz), 115.35 (d, J=24 Hz), 53.52,52.20, 51.81, 48.88, 25.09, 17.71. IR(KBr, cm⁻¹): 2724-2400 (m-s, br),1594 (m), 1138 (s). UV(MeOH): λmax 275 nm, ε 17,400; λmax 268 nm, ε20,800. MS(ESI) m/e 334 (base, M+H⁺). HRMS(CI, NH₃) m/e Calc'd for(M+H⁺):334.1277. Found: 334.1266.

Example 30

2-((1-(4-Fluorophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline(1:1) hydrochloride salt.

Part A: 1-(4-Fluorophenylsulfonyl)-4-oxopiperidine (30A).

4-Piperidone·HCl hydrate (8.0 g, 52 mmol), 4-fluorobenzenesulfonylchloride (10 g, 52 mmol), and 1.0 M NaOH (120 mL) were stirred in THF(200 mL) from 0° C. to RT overnight. After phase separation, the aqueouslayer was extracted further with EtOAc (1 L). The combined organicphases were extracted with 1 M HCl (180 mL), H₂O (100 mL), and brine (50mL). The solution was dried (Na₂SO₄), filtered, and concentrated invacuo to yield sulfonamide 30A (12.1 g) as a pale yellow solid.MS(GC-MS, H₂O) m/e 258 (base, M+H⁺), 188 (13%). HRMS(CI, NH₃) m/e Calc'dfor (M+H⁺: 258.0600. Found: 258.0601.

Part B:2-((l-(4-Fluorophenylsulfonyl)-4-piperidyl))-1,2,3,4-tetrahydroisoquinoline(1:1) hydrochloride salt (30).

Crude ketone 30A (6.0 g, 23 mmol) and titanium (IV) isopropoxide (8.5mL, 29 mmol) were stirred at RT under N₂ for 1 h. Absolute EtOH (25 mL)and sodium cyanoborohydride (0.97 g, 15 mmol) were added, and theresulting mixture was stirred overnight. More NaBH₃CN (1.0 g) was added,and stirring was continued for 1 h. The reaction was quenched with 1 MNaOH (5 mL), filtered through a Celite pad, and rinsed well with MeOH.After concentration, the product was purified by flash chromatography onsilica gel 60, eluting with hexane to 9:1 EtOAc/hexane to yield the freebase amine (1.7 g) as a pale yellow solid. Hydrochloride salt formationas usual, followed by recrystallization from MeOH afforded salt 30 (1.0g) as a colorless solid. m.p.>240°. Elemental analysis. Calc'd forC₂OH₂₄ClFN₂O₂S: C, 58.46; H, 5.90; Cl, 8.64; N, 6.83; F, 4.62; S, 7.80.Found: C, 58.48; H, 5.93; Cl, 8.30; N, 6.80; F, 4.33; S, 7.44. ¹HNMR(300 MHz, DMSO-d₆, δ): 11.70 (br s, 1H), 7.88-7.82 (m, 2H), 7.56-7.49(m, 2H), 7.27-7.17 (m, 4H), 4.40-4.30 (m, 2H), 3.82-3.78 (m, 3H),3.67-3.59 (m, 1H), 3.40-3.22 (m, 2H), 3.02-2.94 (m, 1H), 2.33-2.20 (m,4H), 1.96-1.81 (m, 2H). ¹³C NMR(300 MHz, DMSO-d₆, δ): 165.16 (d, J=251Hz), 132.20, 131.93, 131.06, (d, J=10 Hz), 129.01, 128.80, 127.92,127.13, 126.95, 117.12 (d, J=23 Hz), 60.58, 48.84, 46.35, 45.16, 25.93,25.40. IR(KBr, cm⁻¹): 2800-2300 (m, br), 1592 (m), 1328 (m), 1170 (s).UV(MeOH): λmax 225 nm, ε 10,000. MS(ESI) m/e 375 (base, M+H⁺). HRMS(CI,NH₃) m/e Calc'd for M+H⁺): 375.1543. Found: 375.1525.

The following tables contain examples of the present invention. Thevalues of p and q are taken to be 1-3. When no substitution is desired,R^(1a) and R⁵ are designated as hydrogen.

TABLE 1

Ex R¹ X Y n B + A MS 1 4-fluoro- 1,3- n-propyl 1 1,3- 328 phenyldioxolan- dihydro- 2-yl isoindole 2 4-bromo- 1,3- n-propyl 1 1,3- 390.1phenyl dioxolan- dihydro- 2-yl isoindole 3 4-methyl- 1,3- n-propyl 11,3- 324.2 phenyl dioxolan- dihydro- 2-yl isoindole 4 4-fluoro- 1,3-n-propyl 2 1,2,3,4- 342.2 phenyl dioxolan- tetrahydro- 2-yl iso-quinoline 5 4-fluoro- —C(═O)— n-propyl 1 1,3- 284.1 phenyl dihydro-isoindole 9 4-fluoro- —CH(OH)— n-propyl 1 1,3- 286.2 phenyl dihydro-isoindole 10 4-fluoro- —CH(OAc)— n-propyl 1 1,3- 328.2 phenyl dihydro-isoindole 11 4-fluoro- —C(═O)— n-propyl 2 1,2,3,4- 298.2 phenyltetrahydro- iso- quinoline 12 4-fluoro- —C(═O)— n-propyl 1 1,3- 334.2phenyl dihydro- benz[f]isoi ndole 13 4-pyridyl —C(═O)— n-propyl 21,2,3,4- 281.2 tetrahydro- iso- quinoline 14 3-fluoro- —C(═O)— n-propyl2 1,2,3,4- 298.2 phenyl tetrahydro- iso- quinoline 15 3-fluoro- —C(═O)—n-propyl 1 1,3- 283.1 phenyl dihydro- isoindole 16 4-fluoro- —C(═O)—n-propyl 2 1,3- 333.2 phenyl dihydro- benz[de]iso- indole 17 2-thienyl—C(═O)— n-propyl 2 1,2,3,4- 286.1 tetrahydro- iso- quinoline 184-fluoro- —C(═O)— n-propyl 2 6,7- 358.2 phenyl dimethoxy- 1,2,3,4-tetrahydro- iso- quinoline 19 4-fluoro- —C(═O)— n-propyl 2 (+/−)-trans304.2 phenyl perhydro- iso- quinoline 20 1,3-Dihydro-2H- n-propyl 21,2,3,4- 308.2 benzimidazol-2-one)- tetrahydro- 1-yl iso- quinoline 213-phenyl- —CH₂— 2 1,2,3,4- 290.1 isoxazol-5-yl tetrahydro- iso-quinoline 22 3-(4-Fluorophenyl)- —CH₂— 2 1,2,3,4- 311.22-isoxazolin-5-yl tetrahydro- iso- quinoline 23 4-fluoro- —O— n-propyl 11,3- 272.1 phenyl dihydro- isoindole 24 4-fluoro- —S— n-propyl 21,2,3,4- 302.1 phenyl tetrahydro- iso- quinoline 25 4-fluoro- —S—n-propyl 1 1,3- 288.1 phenyl dihydro- isoindole 26 4-fluoro- —SO₂—n-propyl 1 1,3- 320.1 phenyl dihydro- isoindole 27 4-fluoro- —SO₂—n-propyl 2 1,2,3,4- 334.1 phenyl tetrahydro- iso- quinoline 28 3-fluoro-—S— n-propyl 2 1,2,3,4- 302.1 phenyl tetrahydro- iso- quinoline 293-fluoro- —SO₂— n-propyl 2 1,2,3,4- 334.1 phenyl tetrahydro- iso-quinoline 30 4-fluoro- phenyl —SO₂—

2 1,2,3,4- tetrahydro- iso- quinoline 375.2

TABLE 2

X—Y

Ex. # R^(1a) n R⁵ 1 H 1 2-CH₃ 2 H 1 3-CH₃ 3 H 1 2-CH₂CH₃ 4 H 1 3-CH₂CH₃5 H 1 2-CH₂CH₂CH₃ 6 H 1 3-CH₂CH₂CH₃ 7 H 1 2-isopropyl 8 H 1 3-isopropyl9 H 1 2-butyl 10 H 1 3-butyl 11 H 1 2-isobutyl 12 H 1 3-isobutyl 13 H 12-t-butyl 14 H 1 3-t-butyl 15 H 1 2-Cl 16 H 1 3-Cl 17 H 1 2-F 18 H 1 3-F19 H 1 2-Br 20 H 1 3-Br 21 H 1 2-OCH₃ 22 H 1 3-OCH₃ 23 H 1 2,3-CH₃ 24 H1 2,4-CH₃ 25 H 1 2,5-CH₃ 26 H 1 3,4-CH₃ 27 H 1 2,3-Cl 28 H 1 2,4-Cl 29 H1 2,5-Cl 30 H 1 3,4-Cl 31 H 1 2,3-F 32 H 1 2,4-F 33 H 1 2,5-F 34 H 13,4-F 35 H 1 2,3-Br 36 H 1 2,4-Br 37 H 1 2,5-Br 38 H 1 3,4-Br 39 H 12,3-OCH₃ 40 H 1 2,4-OCH₃ 41 H 1 2,5-OCH₃ 42 H 1 3,4-OCH₃ 43 4-F 1 2-CH₃44 4-F 1 3-CH₃ 45 4-F 1 2-CH₂CH₃ 46 4-F 1 3-CH₂CH₃ 47 4-F 1 2-CH₂CH₂CH₃48 4-F 1 3-CH₂CH₂CH₃ 49 4-F 1 2-isopropyl 50 4-F 1 3-isopropyl 51 4-F 12-butyl 52 4-F 1 3-butyl 53 4-F 1 2-isobutyl 54 4-F 1 3-isobutyl 55 4-F1 2-t-butyl 56 4-F 1 3-t-butyl 57 4-F 1 2-Cl 58 4-F 1 3-Cl 59 4-F 1 2-F60 4-F 1 3-F 61 4-F 1 2-Br 62 4-F 1 3-Br 63 4-F 1 2-OCH₃ 64 4-F 1 3-OCH₃65 4-F 1 2,3-CH₃ 66 4-F 1 2,4-CH₃ 67 4-F 1 2,5-CH₃ 68 4-F 1 3,4-CH₃ 694-F 1 2,3-Cl 70 4-F 1 2,4-Cl 71 4-F 1 2,5-Cl 72 4-F 1 3,4-Cl 73 4-F 12,3-F 74 4-F 1 2,4-F 75 4-F 1 2,5-F 76 4-F 1 3,4-F 77 4-F 1 2,3-Br 784-F 1 2,4-Br 79 4-F 1 2,5-Br 80 4-F 1 3,4-Br 81 4-F 1 2,3-OCH₃ 82 4-F 12,4-OCH₃ 83 4-F 1 2,5-OCH₃ 84 4-F 1 3,4-OCH₃ 85 3-F 1 2-CH₃ 86 3-F 13-CH₃ 87 3-F 1 2-CH₂CH₃ 88 3-F 1 3-CH₂CH₃ 89 3-F 1 2-CH₂CH₂CH₃ 90 3-F 13-CH₂CH₂CH₃ 91 3-F 1 2-isopropyl 92 3-F 1 3-isopropyl 93 3-F 1 2-butyl94 3-F 1 3-butyl 95 3-F 1 2-isobutyl 96 3-F 1 3-isobutyl 97 3-F 12-t-butyl 98 3-F 1 2-t-butyl 99 3-F 1 2-Cl 100 3-F 1 3-Cl 101 3-F 1 2-F102 3-F 1 3-F 103 3-F 1 2-Br 104 3-F 1 3-Br 105 3-F 1 2-OCH₃ 106 3-F 13-OCH₃ 107 3-F 1 2,3-CH₃ 108 3-F 1 2,4-CH₃ 109 3-F 1 2,5-CH₃ 110 3-F 13,4-CH₃ 111 3-F 1 2,3-Cl 112 3-F 1 2,4-Cl 113 3-F 1 2,5-Cl 114 3-F 13,4-Cl 115 3-F 1 2,3-F 116 3-F 1 2,4-F 117 3-F 1 2,5-F 118 3-F 1 3,4-F119 3-F 1 2,3-Br 120 3-F 1 2,4-Br 121 3-F 1 2,5-Br 122 3-F 1 3,4-Br 1233-F 1 2,3-OCH₃ 124 3-F 1 2,4-OCH₃ 125 3-F 1 2,5-OCH₃ 126 3-F 1 3,4-OCH₃127 2,3-F 1 2-CH₃ 128 2,3-F 1 3-CH₃ 129 2,3-F 1 2-CH₂CH₃ 130 2,3-F 13-CH₂CH₃ 131 2,3-F 1 2-CH₂CH₂CH₃ 132 2,3-F 1 3-CH₂CH₂CH₃ 133 2,3-F 12-isopropyl 134 2,3-F 1 3-isopropyl 135 2,3-F 1 2-butyl 136 2,3-F 13-butyl 137 2,3-F 1 2-isobutyl 138 2,3-F 1 3-isobutyl 139 2,3-F 12-t-butyl 140 2,3-F 1 3-t-butyl 141 2,3-F 1 2-Cl 142 2,3-F 1 3-Cl 1432,3-F 1 2-F 144 2,3-F 1 3-F 145 2,3-F 1 2-Br 146 2,3-F 1 3-Br 147 2,3-F1 2-OCH₃ 148 2,3-F 1 3-OCH₃ 149 2,3-F 1 2,3-CH₃ 150 2,3-F 1 2,4-CH₃ 1512,3-F 1 2,5-CH₃ 152 2,3-F 1 3,4-CH₃ 153 2,3-F 1 2,3-Cl 154 2,3-F 12,4-Cl 155 2,3-F 1 2,5-Cl 156 2,3-F 1 3,4-Cl 157 2,3-F 1 2,3-F 158 2,3-F1 2,4-F 159 2,3-F 1 2,5-F 160 2,3-F 1 3,4-F 161 2,3-F 1 2,3-Br 162 2,3-F1 2,4-Br 163 2,3-F 1 2,5-Br 164 2,3-F 1 3,4-Br 165 2,3-F 1 2,3-OCH₃ 1662,3-F 1 2,4-OCH₃ 167 2,3-F 1 2,5-OCH₃ 168 2,3-F 1 3,4-OCH₃ 169 3,4-F 12-CH₃ 170 3,4-F 1 3-CH₃ 171 3,4-F 1 2-CH₂CH₃ 172 3,4-F 1 3-CH₂CH₃ 1733,4-F 1 2-CH₂CH₂CH₃ 174 3,4-F 1 3-CH₂CH₂CH₃ 175 3,4-F 1 2-isopropyl 1763,4-F 1 3-isopropyl 177 3,4-F 1 2-butyl 178 3,4-F 1 3-butyl 179 3,4-F 12-isobutyl 180 3,4-F 1 3-isobutyl 181 3,4-F 1 2-t-butyl 182 3,4-F 13-t-butyl 183 3,4-F 1 2-Cl 184 3,4-F 1 3-Cl 185 3,4-F 1 2-F 186 3,4-F 13-F 187 3,4-F 1 2-Br 188 3,4-F 1 3-Br 189 3,4-F 1 2-OCH₃ 190 3,4-F 13-OCH₃ 191 3,4-F 1 2,3-CH₃ 192 3,4-F 1 2,4-CH₃ 193 3,4-F 1 2,5-CH₃ 1943,4-F 1 3,4-CH₃ 195 3,4-F 1 2,3-Cl 196 3,4-F 1 2,4-Cl 197 3,4-F 1 2,5-Cl198 3,4-F 1 3,4-Cl 199 3,4-F 1 2,3-F 200 3,4-F 1 2,4-F 201 3,4-F 1 2,5-F202 3,4-F 1 3,4-F 203 3,4-F 1 2,3-Br 204 3,4-F 1 2,4-Br 205 3,4-F 12,5-Br 206 3,4-F 1 3,4-Br 207 3,4-F 1 2,3-OCH₃ 208 3,4-F 1 2,4-OCH₃ 2093,4-F 1 2,5-OCH₃ 210 3,4-F 1 3,4-OCH₃ 211 4-Cl 1 2-CH₃ 212 4-Cl 1 3-CH₃213 4-Cl 1 2-CH₂CH₃ 214 4-Cl 1 3-CH₂CH₃ 215 4-Cl 1 2-CH₂CH₂CH₃ 216 4-Cl1 3-CH₂CH₂CH₃ 217 4-Cl 1 2-isopropyl 218 4-Cl 1 3-isopropyl 219 4-Cl 12-butyl 220 4-Cl 1 3-butyl 221 4-Cl 1 2-isobutyl 222 4-Cl 1 3-isobutyl223 4-Cl 1 3-t-butyl 224 4-Cl 1 3-t-butyl 225 4-Cl 1 2-Cl 226 4-Cl 13-Cl 227 4-Cl 1 2-F 228 4-Cl 1 3-F 229 4-Cl 1 2-Br 230 4-Cl 1 3-Br 2314-Cl 1 2-OCH₃ 232 4-Cl 1 3-OCH₃ 233 4-Cl 1 2,3-CH₃ 234 4-Cl 1 2,4-CH₃235 4-Cl 1 2,5-CH₃ 236 4-Cl 1 3,4-CH₃ 237 4-Cl 1 2,3-Cl 238 4-Cl 12,4-Cl 239 4-Cl 1 2,5-Cl 240 4-Cl 1 3,4-Cl 241 4-Cl 1 2,3-F 242 4-Cl 12,4-F 243 4-Cl 1 2,5-F 244 4-Cl 1 3,4-F 245 4-Cl 1 2,3-Br 246 4-Cl 12,4-Br 247 4-Cl 1 2,5-Br 248 4-Cl 1 3,4-Br 249 4-Cl 1 2,3-OCH₃ 250 4-Cl1 2,4-OCH₃ 251 4-Cl 1 2,5-OCH₃ 252 4-Cl 1 3,4-OCH₃ 253 3-Cl 1 2-CH₃ 2543-Cl 1 3-CH₃ 255 3-Cl 1 2-CH₂CH₃ 256 3-Cl 1 3-CH₂CH₃ 257 3-Cl 12-CH₂CH₂CH₃ 258 3-Cl 1 3-CH₂CH₂CH₃ 259 3-Cl 1 2-isopropyl 260 3-Cl 13-isopropyl 261 3-Cl 1 2-butyl 262 3-Cl 1 3-butyl 263 3-Cl 1 2-isobutyl264 3-Cl 1 3-isobutyl 265 3-Cl 1 2-t-butyl 266 3-Cl 1 3-t-butyl 267 3-Cl1 2-Cl 268 3-Cl 1 3-Cl 269 3-Cl 1 2-F 270 3-Cl 1 3-F 271 3-Cl 1 2-Br 2723-Cl 1 3-Br 273 3-Cl 1 2-OCH₃ 274 3-Cl 1 3-OCH₃ 275 3-Cl 1 2,3-CH₃ 2763-Cl 1 2,4-CH₃ 277 3-Cl 1 2,5-CH₃ 278 3-Cl 1 3,4-CH₃ 279 3-Cl 1 2,3-Cl280 3-Cl 1 2,4-Cl 281 3-Cl 1 2,5-Cl 282 3-Cl 1 3,4-Cl 283 3-Cl 1 2,3-F284 3-Cl 1 2,4-F 285 3-Cl 1 2,5-F 286 3-Cl 1 3,4-F 287 3-Cl 1 2,3-Br 2883-Cl 1 2,4-Br 289 3-Cl 1 2,5-Br 290 3-Cl 1 3,4-Br 291 3-Cl 1 2,3-OCH₃292 3-Cl 1 2,4-OCH₃ 293 3-Cl 1 2,5-OCH₃ 294 3-Cl 1 3,4-OCH₃ 295 3-CF₃ 12-CH₃ 296 3-CF₃ 1 3-CH₃ 297 3-CF₃ 1 2-CH₂CH₃ 298 3-CF₃ 1 3-CH₂CH₃ 2993-CF₃ 1 2-CH₂CH₂CH₃ 300 3-CF₃ 1 3-CH₂CH₂CH₃ 301 3-CF₃ 1 2-isopropyl 3023-CF₃ 1 3-isopropyl 303 3-CF₃ 1 2-butyl 304 3-CF₃ 1 3-butyl 305 3-CF₃ 12-isobutyl 306 3-CF₃ 1 3-isobutyl 307 3-CF₃ 1 2-t-butyl 308 3-CF₃ 13-t-butyl 309 3-CF₃ 1 2-Cl 310 3-CF₃ 1 3-Cl 311 3-CF₃ 1 2-F 312 3-CF₃ 13-F 313 3-CF₃ 1 2-Br 314 3-CF₃ 1 3-Br 315 3-CF₃ 1 2-OCH₃ 316 3-CF₃ 13-OCH₃ 317 3-CF₃ 1 2,3-CH₃ 318 3-CF₃ 1 2,4-CH₃ 319 3-CF₃ 1 2,5-CH₃ 3203-CF₃ 1 3,4-CH₃ 321 3-CF₃ 1 2,3-Cl 322 3-CF₃ 1 2,4-Cl 323 3-CF₃ 1 2,5-Cl324 3-CF₃ 1 3,4-Cl 325 3-CF₃ 1 2,3-F 326 3-CF₃ 1 2,4-F 327 3-CF₃ 1 2,5-F328 3-CF₃ 1 3,4-F 329 3-CF₃ 1 2,3-Br 330 3-CF₃ 1 2,4-Br 331 3-CF₃ 12,5-Br 332 3-CF₃ 1 3,4-Br 333 3-CF₃ 1 2,3-OCH₃ 334 3-CF₃ 1 2,4-OCH₃ 3353-CF₃ 1 2,5-OCH₃ 336 3-CF₃ 1 3,4-OCH₃ 337 4-CF₃ 1 2-CH₃ 338 4-CF₃ 13-CH₃ 339 4-CF₃ 1 2-CH₂CH₃ 340 4-CF₃ 1 3-CH₂CH₃ 341 4-CF₃ 1 2-CH₂CH₂CH₃342 4-CF₃ 1 3-CH₂CH₂CH₃ 343 4-CF₃ 1 2-isopropyl 344 4-CF₃ 1 3-isopropyl345 4-CF₃ 1 2-butyl 346 4-CF₃ 1 3-butyl 347 4-CF₃ 1 2-isobutyl 348 4-CF₃1 3-isobutyl 349 4-CF₃ 1 2-t-butyl 350 4-CF₃ 1 3-t-butyl 351 4-CF₃ 12-Cl 352 4-CF₃ 1 3-Cl 353 4-CF₃ 1 2-F 354 4-CF₃ 1 3-F 355 4-CF₃ 1 2-Br356 4-CF₃ 1 3-Br 357 4-CF₃ 1 2-OCH₃ 358 4-CF₃ 1 3-OCH₃ 359 4-CF₃ 12,3-CH₃ 360 4-CF₃ 1 2,4-CH₃ 361 4-CF₃ 1 2,5-CH₃ 362 4-CF₃ 1 3,4-CH₃ 3634-CF₃ 1 2,3-Cl 364 4-CF₃ 1 2,4-Cl 365 4-CF₃ 1 2,5-Cl 366 4-CF₃ 1 3,4-Cl367 4-CF₃ 1 2,3-F 368 4-CF₃ 1 2,4-F 369 4-CF₃ 1 2,5-F 370 4-CF₃ 1 3,4-F371 4-CF₃ 1 2,3-Br 372 4-CF₃ 1 2,4-Br 373 4-CF₃ 1 2,5-Br 374 4-CF₃ 13,4-Br 375 4-CF₃ 1 2,3-OCH₃ 376 4-CF₃ 1 2,4-OCH₃ 377 4-CF₃ 1 2,5-OCH₃378 4-CF₃ 1 3,4-OCH₃ 379 4-CN 1 2-CH₃ 380 4-CN 1 3-CH₃ 381 4-CN 12-CH₂CH₃ 382 4-CN 1 3-CH₂CH₃ 383 4-CN 1 2-CH₂CH₂CH₃ 384 4-CN 13-CH₂CH₂CH₃ 385 4-CN 1 2-isopropyl 386 4-CN 1 3-isopropyl 387 4-CN 12-butyl 388 4-CN 1 3-butyl 389 4-CN 1 2-isobutyl 390 4-CN 1 3-isobutyl391 4-CN 1 2-t-butyl 392 4-CN 1 3-t-butyl 393 4-CN 1 2-Cl 394 4-CN 13-Cl 395 4-CN 1 2-F 396 4-CN 1 3-F 397 4-CN 1 2-Br 398 4-CN 1 3-Br 3994-CN 1 2-OCH₃ 400 4-CN 1 3-OCH₃ 401 4-CN 1 2,3-CH₃ 402 4-CN 1 2,4-CH₃403 4-CN 1 2,5-CH₃ 404 4-CN 1 3,4-CH₃ 405 4-CN 1 2,3-Cl 406 4-CN 12,4-Cl 407 4-CN 1 2,5-Cl 408 4-CN 1 3,4-Cl 409 4-CN 1 2,3-F 410 4-CN 12,4-F 411 4-CN 1 2,5-F 412 4-CN 1 3,4-F 413 4-CN 1 2,3-Br 414 4-CN 12,4-Br 415 4-CN 1 2,5-Br 416 4-CN 1 3,4-Br 417 4-CN 1 2,3-OCH₃ 418 4-CN1 2,4-OCH₃ 419 4-CN 1 2,5-OCH₃ 420 4-CN 1 3,4-OCH₃ 421 3-CN 1 2-CH₃ 4223-CN 1 3-CH₃ 423 3-CN 1 2-CH₂CH₃ 424 3-CN 1 3-CH₂CH₃ 425 3-CN 12-CH₂CH₂CH₃ 426 3-CN 1 3-CH₂CH₂CH₃ 427 3-CN 1 2-isopropyl 428 3-CN 13-isopropyl 429 3-CN 1 2-butyl 430 3-CN 1 3-butyl 431 3-CN 1 2-isobutyl432 3-CN 1 3-isobutyl 433 3-CN 1 2-t-butyl 434 3-CN 1 3-t-butyl 435 3-CN1 2-Cl 436 3-CN 1 3-Cl 437 3-CN 1 2-F 438 3-CN 1 3-F 439 3-CN 1 2-Br 4403-CN 1 3-Br 441 3-CN 1 2-OCH₃ 442 3-CN 1 3-OCH₃ 443 3-CN 1 2,3-CH₃ 4443-CN 1 2,4-CH₃ 445 3-CN 1 2,5-CH₃ 446 3-CN 1 3,4-CH₃ 447 3-CN 1 2,3-Cl448 3-CN 1 2,4-Cl 449 3-CN 1 2,5-Cl 450 3-CN 1 3,4-Cl 451 3-CN 1 2,3-F452 3-CN 1 2,4-F 453 3-CN 1 2,5-F 454 3-CN 1 3,4-F 455 3-CN 1 2,3-Br 4563-CN 1 2,4-Br 457 3-CN 1 2,5-Br 458 3-CN 1 3,4-Br 459 3-CN 1 2,3-OCH₃460 3-CN 1 2,4-OCH₃ 461 3-CN 1 2,5-OCH₃ 462 3-CN 1 3,4-OCH₃ 463 2-F 1 H464 3-F 1 H 465 4-F 1 H 466 2-Cl 1 H 467 3-Cl 1 H 468 4-Cl 1 H 469 2-Br1 H 470 3-Br 1 H 471 4-Br 1 H 472 3,4-F 1 H 473 2,3-F 1 H 474 2,4-F 1 H475 2-CN 1 H 476 3-CN 1 H 477 4-CN 1 H 478 2-CF₃ 1 H 479 3-CF₃ 1 H 4804-CF₃ 1 H 481 H 1 H 482 2-OCH₃ 1 H 483 3-OCH₃ 1 H 484 4-OCH₃ 1 H 4852-CH₃ 1 H 486 3-CH₃ 1 H 487 4-CH₃ 1 H 488 4-F 2 2-CH₃ 489 4-F 2 3-CH₃490 4-F 2 2-CH₂CH₃ 491 4-F 2 3-CH₂CH₃ 492 4-F 2 2-CH₂CH₂CH₃ 493 4-F 23-CH₂CH₂CH₃ 494 4-F 2 2-isopropyl 495 4-F 2 3-isopropyl 496 4-F 22-butyl 497 4-F 2 3-butyl 498 4-F 2 2-isobutyl 499 4-F 2 3-isobutyl 5004-F 2 2-t-butyl 601 4-F 2 3-t-butyl 602 4-F 2 2-Cl 603 4-F 2 3-Cl 6044-F 2 2-F 605 4-F 2 3-F 606 4-F 2 2-Br 607 4-F 2 3-Br 608 4-F 2 2-OCH₃609 4-F 2 3-OCH₃ 610 4-F 2 2,3-CH₃ 611 4-F 2 2,4-CH₃ 612 4-F 2 2,5-CH₃613 4-F 2 3,4-CH₃ 614 4-F 2 3,5-CH₃ 615 4-F 2 4,5-CH₃ 616 4-F 2 2,3-Cl617 4-F 2 2,4-Cl 618 4-F 2 2,5-Cl 619 4-F 2 3,4-Cl 620 4-F 2 3,5-Cl 6214-F 2 4,5-Cl 622 4-F 2 2,3-F 623 4-F 2 2,4-F 624 4-F 2 2,5-F 625 4-F 23,4-F 626 4-F 3,5-F 627 4-F 4,5-F 628 4-F 2 2,3-Br 629 4-F 2 2,4-Br 6304-F 2 2,5-Br 631 4-F 2 3,4-Br 632 4-F 2 3,5-Br 633 4-F 2 4,5-Br 634 4-F2 2,3-OCH₃ 635 4-F 2 2,4-OCH₃ 636 4-F 2 2,5-OCH₃ 637 4-F 2 3,4-OCH₃ 6384-F 2 3,5-OCH₃ 639 4-F 2 4,5-OCH₃ 640 3-F 2 2-CH₃ 641 3-F 2 3-CH₃ 6423-F 2 2-CH₂CH₃ 643 3-F 2 3-CH₂CH₃ 644 3-F 2 2-CH₂CH₂CH₃ 645 3-F 23-CH₂CH₂CH₃ 646 3-F 2 2-isopropyl 647 3-F 2 3-isopropyl 648 3-F 22-butyl 649 3-F 2 3-butyl 650 3-F 2 2-isobutyl 651 3-F 2 3-isobutyl 6523-F 2 2-t-butyl 653 3-F 2 3-t-butyl 654 3-F 2 2-Cl 655 3-F 2 3-Cl 6563-F 2 2-F 657 3-F 2 3-F 658 3-F 2 2-Br 659 3-F 2 3-Br 660 3-F 2 2-OCH₃661 3-F 2 3-OCH₃ 662 3-F 2 2,3-CH₃ 663 3-F 2 2,4-CH₃ 664 3-F 2 2,5-CH₃665 3-F 2 3,4-CH₃ 666 3-F 2 2,3-Cl 667 3-F 2 2,4-Cl 668 3-F 2 2,5-Cl 6693-F 2 3,4-Cl 670 3-F 2 2,3-F 671 3-F 2 2,4-F 672 3-F 2 2,5-F 673 3-F 23,4-F 674 3-F 2 2,3-Br 675 3-F 2 2,4-Br 676 3-F 2 2,5-Br 677 3-F 23,4-Br 678 3-F 2 2,3-OCH₃ 679 3-F 2 2,4-OCH₃ 680 3-F 2 2,5-OCH₃ 681 3-F2 3,4-OCH₃ 682 2,3-F 2 2-CH₃ 683 2,3-F 2 3-CH₃ 684 2,3-F 2 2-CH₂CH₃ 6852,3-F 2 3-CH₂CH₃ 686 2,3-F 2 2-CH₂CH₂CH₃ 687 2,3-F 2 3-CH₂CH₂CH₃ 6882,3-F 2 2-isopropyl 689 2,3-F 2 3-isopropyl 690 2,3-F 2 2-butyl 6912,3-F 2 3-butyl 692 2,3-F 2 2-isobutyl 693 2,3-F 2 3-isobutyl 694 2,3-F2 2-t-butyl 695 2,3-F 2 3-t-butyl 696 2,3-F 2 2-Cl 697 2,3-F 2 3-Cl 6982,3-F 2 2-F 699 2,3-F 2 3-F 700 2,3-F 2 2-Br 701 2,3-F 2 3-Br 702 2,3-F2 2-OCH₃ 703 2,3-F 2 3-OCH₃ 704 2,3-F 2 2,3-CH₃ 705 2,3-F 2 2,4-CH₃ 7062,3-F 2 2,5-CH₃ 707 2,3-F 2 3,4-CH₃ 708 2,3-F 2 2,3-Cl 709 2,3-F 22,4-Cl 710 2,3-F 2 2,5-Cl 711 2,3-F 2 3,4-Cl 712 2,3-F 2 2,3-F 713 2,3-F2 2,4-F 714 2,3-F 2 2,5-F 715 2,3-F 2 3,4-F 716 2,3-F 2 2,3-Br 717 2,3-F2 2,4-Br 718 2,3-F 2 2,5-Br 719 2,3-F 2 3,4-Br 720 2,3-F 2 2,3-OCH₃ 7212,3-F 2 2,4-OCH₃ 722 2,3-F 2 2,5-OCH₃ 723 2,3-F 2 3,4-OCH₃ 724 3,4-F 22-CH₃ 725 3,4-F 2 3-CH₃ 726 3,4-F 2 2-CH₂CH₃ 727 3,4-F 2 3-CH₂CH₃ 7283,4-F 2 2-CH₂CH₂CH₃ 729 3,4-F 2 3-CH₂CH₂CH₃ 730 3,4-F 2 2-isopropyl 7313,4-F 2 3-isopropyl 732 3,4-F 2 2-butyl 733 3,4-F 2 3-butyl 734 3,4-F 22-isobutyl 735 3,4-F 2 3-isobutyl 736 3,4-F 2 2-t-butyl 737 3,4-F 23-t-butyl 738 3,4-F 2 2-Cl 739 3,4-F 2 3-Cl 740 3,4-F 2 2-F 741 3,4-F 23-F 742 3,4-F 2 2-Br 743 3,4-F 2 3-Br 744 3,4-F 2 2-OCH₃ 745 3,4-F 23-OCH₃ 746 3,4-F 2 2,3-CH₃ 747 3,4-F 2 2,4-CH₃ 748 3,4-F 2 2,5-CH₃ 7493,4-F 2 3,4-CH₃ 750 3,4-F 2 2,3-Cl 751 3,4-F 2 2,4-Cl 752 3,4-F 2 2,5-Cl753 3,4-F 2 3,4-Cl 754 3,4-F 2 2,3-F 755 3,4-F 2 2,4-F 756 3,4-F 2 2,5-F757 3,4-F 2 3,4-F 758 3,4-F 2 2,3-Br 759 3,4-F 2 2,4-Br 760 3,4-F 22,5-Br 761 3,4-F 2 3,4-Br 762 3,4-F 2 2,3-OCH₃ 763 3,4-F 2 2,4-OCH₃ 7643,4-F 2 2,5-OCH₃ 765 3,4-F 2 3,4-OCH₃ 766 4-Cl 2 2-CH₃ 767 4-Cl 2 3-CH₃768 4-Cl 2 2-CH₂CH₃ 769 4-Cl 2 3-CH₂CH₃ 770 4-Cl 2 2-CH₂CH₂CH₃ 771 4-Cl2 3-CH₂CH₂CH₃ 772 4-Cl 2 2-isopropyl 773 4-Cl 2 3-isopropyl 774 4-Cl 22-butyl 775 4-Cl 2 3-butyl 776 4-Cl 2 2-isobutyl 777 4-Cl 2 3-isobutyl778 4-Cl 2 2-t-butyl 779 4-Cl 2 3-t-butyl 780 4-Cl 2 2-Cl 781 4-Cl 23-Cl 782 4-Cl 2 2-F 783 4-Cl 2 3-F 784 4-Cl 2 2-Br 785 4-Cl 2 3-Br 7864-Cl 2 2-OCH₃ 787 4-Cl 2 3-OCH₃ 788 4-Cl 2 2,3-CH₃ 789 4-Cl 2 2,4-CH₃790 4-Cl 2 2,5-CH₃ 791 4-Cl 2 3,4-CH₃ 792 4-Cl 2 2,3-Cl 793 4-Cl 22,4-Cl 794 4-Cl 2 2,5-Cl 795 4-Cl 2 3,4-Cl 796 4-Cl 2 2,3-F 797 4-Cl 22,4-F 798 4-Cl 2 2,5-F 799 4-Cl 2 3,4-F 800 4-Cl 2 2,3-Br 801 4-Cl 22,4-Br 802 4-Cl 2 2,5-Br 803 4-Cl 2 3,4-Br 804 4-Cl 2 2,3-OCH₃ 805 4-Cl2 2,4-OCH₃ 806 4-Cl 2 2,5-OCH₃ 807 4-Cl 2 3,4-OCH₃ 808 3-Cl 2 2-CH₃ 8093-Cl 2 3-CH₃ 810 3-Cl 2 2-CH₂CH₃ 811 3-Cl 2 3-CH₂CH₃ 812 3-Cl 22-CH₂CH₂CH₃ 813 3-Cl 2 3-CH₂CH₂CH₃ 814 3-Cl 2 2-isopropyl 815 3-Cl 23-isopropyl 816 3-Cl 2 2-butyl 817 3-Cl 2 3-butyl 818 3-Cl 2 2-isobutyl819 3-Cl 2 3-isobutyl 820 3-Cl 2 2-t-butyl 821 3-Cl 2 3-t-butyl 822 3-Cl2 2-Cl 823 3-Cl 2 3-Cl 824 3-Cl 2 2-F 825 3-Cl 2 3-F 826 3-Cl 2 2-Br 8273-Cl 2 3-Br 828 3-Cl 2 2-OCH₃ 829 3-Cl 2 3-OCH₃ 830 3-Cl 2 2,3-CH₃ 8313-Cl 2 2,4-CH₃ 832 3-Cl 2 2,5-CH₃ 833 3-Cl 2 3,4-CH₃ 834 3-Cl 2 2,3-Cl835 3-Cl 2 2,4-Cl 836 3-Cl 2 2,5-Cl 837 3-Cl 2 2,4-Cl 838 3-Cl 2 2,3-F839 3-Cl 2 2,4-F 840 3-Cl 2 2,5-F 841 3-Cl 2 3,4-F 842 3-Cl 2 2,3-Br 8433-Cl 2 2,4-Br 844 3-Cl 2 2,5-Br 845 3-Cl 2 3,4-Br 846 3-Cl 2 2,3-OCH₃847 3-Cl 2 2,4-OCH₃ 848 3-Cl 2 2,5-OCH₃ 849 3-Cl 2 3,4-OCH₃ 850 3-CF₃ 22-CH₃ 851 3-CF₃ 2 3-CH₃ 852 3-CF₃ 2 2-CH₂CH₃ 853 3-CF₃ 2 3-CH₂CH₃ 8543-CF₃ 2 2-CH₂CH₂CH₃ 855 3-CF₃ 2 3-CH₂CH₂CH₃ 856 3-CF₃ 2 2-isopropyl 8573-CF₃ 2 3-isopropyl 858 3-CF₃ 2 2-butyl 859 3-CF₃ 2 3-butyl 860 3-CF₃ 22-isobutyl 861 3-CF₃ 2 3-isobutyl 862 3-CF₃ 2 2-t-butyl 863 3-CF₃ 23-t-butyl 864 3-CF₃ 2 2-Cl 865 3-CF₃ 2 3-Cl 866 3-CF₃ 2 2-F 867 3-CF₃ 23-F 868 3-CF₃ 2 2-Br 869 3-CF₃ 2 3-Br 870 3-CF₃ 2 2-OCH₃ 871 3-CF₃ 23-OCH₃ 872 3-CF₃ 2 2,3-CH₃ 873 3-CF₃ 2 2,4-CH₃ 874 3-CF₃ 2 2,5-CH₃ 8753-CF₃ 2 3,4-CH₃ 876 3-CF₃ 2 2,3-Cl 877 3-CF₃ 2 2,4-Cl 878 3-CF₃ 2 2,5-Cl879 3-CF₃ 2 3,4-Cl 880 3-CF₃ 2 2,3-F 881 3-CF₃ 2 2,4-F 882 3-CF₃ 2 2,5-F883 3-CF₃ 2 3,4-F 884 3-CF₃ 2 2,3-Br 885 3-CF₃ 2 2,4-Br 886 3-CF₃ 22,5-Br 887 3-CF₃ 2 3,4-Br 888 3-CF₃ 2 2,3-OCH₃ 889 3-CF₃ 2 2,4-OCH₃ 8903-CF₃ 2 2,5-OCH₃ 891 3-CF₃ 2 3,4-OCH₃ 892 4-CF₃ 2 2-CH₃ 893 4-CF₃ 23-CH₃ 894 4-CF₃ 2 2-CH₂CH₃ 895 4-CF₃ 2 3-CH₂CH₃ 896 4-CF₃ 2 2-CH₂CH₂CH₃887 4-CF₃ 2 3-CH₂CH₂CH₃ 898 4-CF₃ 2 2-isopropyl 899 4-CF₃ 2 3-isopropyl900 4-CF₃ 2 2-butyl 901 4-CF₃ 2 3-butyl 902 4-CF₃ 2 2-isobutyl 903 4-CF₃2 3-isobutyl 904 4-CF₃ 2 2-t-butyl 905 4-CF₃ 2 3-t-butyl 906 4-CF₃ 22-Cl 907 4-CF₃ 2 3-Cl 908 4-CF₃ 2 2-F 909 4-CF₃ 2 3-F 910 4-CF₃ 2 2-Br911 4-CF₃ 2 3-Br 912 4-CF₃ 2 2-OCH₃ 913 4-CF₃ 2 3-OCH₃ 914 4-CF₃ 22,3-CH₃ 915 4-CF₃ 2 2,4-CH₃ 916 4-CF₃ 2 2,5-CH₃ 917 4-CF₃ 2 3,4-CH₃ 9184-CF₃ 2 2,3-Cl 919 4-CF₃ 2 2,4-Cl 920 4-CF₃ 2 2,5-Cl 921 4-CF₃ 2 3,4-Cl922 4-CF₃ 2 2,3-F 923 4-CF₃ 2 2,4-F 924 4-CF₃ 2 2,5-F 925 4-CF₃ 2 3,4-F926 4-CF₃ 2 2,3-Br 927 4-CF₃ 2 2,4-Br 928 4-CF₃ 2 2,5-Br 929 4-CF₃ 23,4-Br 930 4-CF₃ 2 2,3-OCH₃ 931 4-CF₃ 2 2,4-OCH₃ 932 4-CF₃ 2 2,5-OCH₃933 4-CF₃ 2 3,4-OCH₃ 934 4-CN 2 2-CH₃ 935 4-CN 2 3-CH₃ 936 4-CN 22-CH₂CH₃ 937 4-CN 2 3-CH₂CH₃ 938 2-CN 2 2-CH₂CH₂CH₃ 939 4-CN 23-CH₂CH₂CH₃ 940 4-CN 2 2-isopropyl 941 4-CN 2 3-isopropyl 942 4-CN 22-butyl 943 4-CN 2 3-butyl 944 4-CN 2 2-isobutyl 945 4-CN 2 3-isobutyl946 4-CN 2 2-t-butyl 947 4-CN 2 3-t-butyl 948 4-CN 2 2-Cl 949 4-CN 23-Cl 950 4-CN 2 2-F 951 4-CN 2 3-F 952 4-CN 2 2-Br 953 4-CN 2 3-Br 9544-CN 2 2-OCH₃ 955 4-CN 2 3-OCH₃ 956 4-CN 2 2,3-CH₃ 957 4-CN 2 2,4-CH₃958 4-CN 2 2,5-CH₃ 959 4-CN 2 3,4-CH₃ 960 4-CN 2 2,3-Cl 961 4-CN 22,4-Cl 962 4-CN 2 2,5-Cl 963 4-CN 2 3,4-Cl 964 4-CN 2 2,3-F 965 4-CN 22,4-F 966 4-CN 2 2,5-F 967 4-CN 2 3,4-F 968 4-CN 2 2,3-Br 969 4-CN 22,4-Br 970 4-CN 2 2,5-Br 971 4-CN 2 3,4-Br 972 4-CN 2 2,3-OCH₃ 973 4-CN2 2,4-OCH₃ 974 4-CN 2 2,5-OCH₃ 975 4-CN 2 3,4-OCH₃ 976 3-CN 2 2-CH₃ 9773-CN 2 3-CH₃ 978 3-CN 2 2-CH₂CH₃ 979 3-CN 2 3-CH₂CH₃ 980 3-CN 22-CH₂CH₂CH₃ 981 3-CN 2 3-CH₂CH₂CH₃ 982 3-CN 2 2-isopropyl 983 3-CN 23-isopropyl 984 3-CN 2 2-butyl 985 3-CN 2 3-butyl 986 3-CN 2 2-isobutyl987 3-CN 2 3-isobutyl 988 3-CN 2 2-t-butyl 989 3-CN 2 3-t-butyl 990 3-CN2 2-Cl 991 3-CN 2 3-Cl 992 3-CN 2 2-F 993 3-CN 2 3-F 994 3-CN 2 2-Br 9953-CN 2 3-Br 996 3-CN 2 2-OCH₃ 997 3-CN 2 3-OCH₃ 998 3-CN 2 2,3-CH₃ 9993-CN 2 2,4-CH₃ 1000 3-CN 2 2,5-CH₃ 1001 3-CN 2 3,4-CH₃ 1002 3-CN 22,3-Cl 1003 3-CN 2 2,4-Cl 1004 3-CN 2 2,5-Cl 1005 3-CN 2 3,4-Cl 10063-CN 2 2,3-F 1007 3-CN 2 2,4-F 1008 3-CN 2 2,5-F 1009 3-CN 2 3,4-F 10103-CN 2 2,3-Br 1011 3-CN 2 2,4-Br 1012 3-CN 2 2,5-Br 1013 3-CN 2 3,4-Br1014 3-CN 2 2,3-OCH₃ 1015 3-CN 2 2,4-OCH₃ 1016 3-CN 2 2,5-OCH₃ 1017 3-CN2 3,4-OCH₃ 1018 2-F 2 H 1019 3-F 2 H 1020 4-F 2 H 1021 2-Cl 2 H 10223-Cl 2 H 1023 4-Cl 2 H 1024 2-Br 2 H 1025 3-Br 2 H 1026 4-Br 2 H 10273,4-F 2 H 1028 2,3-F 2 H 1029 2,4-F 2 H 1030 2-CN 2 H 1031 3-CN 2 H 10324-CN 2 H 1033 2-CF₃ 2 H 1034 3-CF₃ 2 H 1035 4-CF₃ 2 H 1036 H 2 H 10372-OCH₃ 2 H 1038 3-OCH₃ 2 H 1039 4-OCH₃ 2 H 1040 2-CH₃ 2 H 1041 3-CH₃ 2 H1042 4-CH₃ 2 H 1043 2-F 2 3,4-fused phenyl 1044 3-F 2 3,4-fused phenyl1045 4-F 2 3,4-fused phenyl 1046 2-Cl 2 3,4-fused phenyl 1047 3-Cl 23,4-fused phenyl 1048 4-Cl 2 3,4-fused phenyl 1049 2-Br 2 3,4-fusedphenyl 1050 3-Br 2 3,4-fused phenyl 1051 4-Br 2 3,4-fused phenyl 10523,4-F 2 3,4-fused phenyl 1053 2,3-F 2 3,4-fused phenyl 1054 2,4-F 23,4-fused phenyl 1055 2-CN 2 3,4-fused phenyl 1056 3-CN 2 3,4-fusedphenyl 1057 4-CN 2 3,4-fused phenyl 1058 2-CF₃ 2 3,4-fused phenyl 10593-CF₃ 2 3,4-fused phenyl 1060 4-CF₃ 2 3,4-fused phenyl 1061 H 23,4-fused phenyl 1062 2-OCH₃ 2 3,4-fused phenyl 1063 3-OCH₃ 2 3,4-fusedphenyl 1064 4-OCH₃ 2 3,4-fused phenyl 1065 2-CH₃ 2 3,4-fused phenyl 10663-CH₃ 2 3,4-fused phenyl 1067 4-CH₃ 2 3,4-fused phenyl 1068 2-F 13,4-fused phenyl 1069 3-F 1 3,4-fused phenyl 1070 4-F 1 3,4-fused phenyl1071 2-Cl 1 3,4-fused phenyl 1072 3-Cl 1 3,4-fused phenyl 1073 4-Cl 13,4-fused phenyl 1074 2-Br 1 3,4-fused phenyl 1075 3-Br 1 3,4-fusedphenyl 1076 4-Br 1 3,4-fused phenyl 1077 3,4-F 1 3,4-fused phenyl 10782,3-F 1 3,4-fused phenyl 1079 2,4-F 1 3,4-fused phenyl 1080 2-CN 13,4-fused phenyl 1081 3-CN 1 3,4-fused phenyl 1082 4-CN 1 3,4-fusedphenyl 1083 2-CF₃ 1 3,4-fused phenyl 1084 3-CF₃ 1 3,4-fused phenyl 10854-CF₃ 1 3,4-fused phenyl 1086 H 1 3,4-fused phenyl 1087 2-OCH₃ 13,4-fused phenyl 1088 3-OCH₃ 1 3,4-fused phenyl 1089 4-OCH₃ 1 3,4-fusedphenyl 1090 2-CH₃ 1 3,4-fused phenyl 1091 3-CH₃ 1 3,4-fused phenyl 10924-CH₃ 1 3,4-fused phenyl 1093 2-F 2 Q 1094 3-F 2 Q 1095 4-F 2 Q 10962-Cl 2 Q 1097 3-Cl 2 Q 1098 4-Cl 2 Q 1099 2-Br 2 Q 1100 3-Br 2 Q 11014-Br 2 Q 1102 3,4-F 2 Q 1103 2,3-F 2 Q 1104 2,4-F 2 Q 1105 2-CN 2 Q 11063-CN 2 Q 1107 4-CN 2 Q 1108 2-CF₃ 2 Q 1109 3-CF₃ 2 Q 1110 4-CF₃ 2 Q 1111H 2 Q 1112 2-OCH₃ 2 Q 1113 3-OCH₃ 2 Q 1114 4-OCH₃ 2 Q 1115 2-CH₃ 2 Q1116 3-CH₃ 2 Q 1117 4-CH₃ 2 Q 1118 2-F 1 2,3-fused phenyl 1119 3-F 12,3-fused phenyl 1120 4-F 1 2,3-fused phenyl 1121 2-Cl 1 2,3-fusedphenyl 1122 3-Cl 1 2,3-fused phenyl 1123 4-Cl 1 2,3-fused phenyl 11242-Br 1 2,3-fused phenyl 1125 3-Br 1 2,3-fused phenyl 1126 4-Br 12,3-fused phenyl 1127 3,4-F 1 2,3-fused phenyl 1128 2,3-F 1 2,3-fusedphenyl 1129 2,4-F 1 2,3-fused phenyl 1130 2-CN 1 2,3-fused phenyl 11313-CN 1 2,3-fused phenyl 1132 4-CN 1 2,3-fused phenyl 1133 2-CF₃ 12,3-fused phenyl 1134 3-CF₃ 1 2,3-fused phenyl 1135 4-CF₃ 1 2,3-fusedphenyl 1136 H 1 2,3-fused phenyl 1137 2-OCH₃ 1 2,3-fused phenyl 11383-OCH₃ 1 2,3-fused phenyl 1139 4-OCH₃ 1 2,3-fused phenyl 1140 2-CH₃ 12,3-fused phenyl 1141 3-CH₃ 1 2,3-fused phenyl 1142 4-CH₃ 1 2,3-fusedphenyl 1143 2-F 2 2,3-fused phenyl 1144 3-F 2 2,3-fused phenyl 1145 4-F2 2,3-fused phenyl 1146 2-Cl 2 2,3-fused phenyl 1147 3-Cl 2 2,3-fusedphenyl 1148 4-Cl 2 2,3-fused phenyl 1149 4-Cl 2 2,3-fused phenyl 11492-Br 2 2,3-fused phenyl 1150 3-Br 2 2,3-fused phenyl 1151 4-Br 22,3-fused phenyl 1152 3,4-F 2 2,3-fused phenyl 1153 2,3-F 2 2,3-fusedphenyl 1154 2,4-F 2 2,3-fused phenyl 1155 2-CN 2 2,3-fused phenyl 11563-CN 2 2,3-fused phenyl 1157 4-CN 2 2,3-fused phenyl 1158 2-CF₃ 22,3-fused phenyl 1159 3-CF₃ 2 2,3-fused phenyl 1160 4-CF₃ 2 2,3-fusedphenyl 1161 H 2 2,3-fused phenyl 1162 2-OCH₃ 2 2,3-fused phenyl 11633-OCH₃ 2 2,3-fused phenyl 1164 4-OCH₃ 2 2,3-fused phenyl 1165 2-CH₃ 22,3-fused phenyl 1166 3-CH₃ 2 2,3-fused phenyl 1167 4-CH₃ 2 2,3-fusedphenyl 1168 2-F 2 4,5-fused phenyl 1169 3-F 2 4,5-fused phenyl 1170 4-F2 4,5-fused phenyl 1171 2-Cl 2 4,5-fused phenyl 1172 3-Cl 2 4,5-fusedphenyl 1173 4-Cl 2 4,5-fused phenyl 1174 2-Br 2 4,5-fused phenyl 11753-Br 2 4,5-fused phenyl 1176 4-Br 2 4,5-fused phenyl 1177 3,4-F 24,5-fused phenyl 1178 2,3-F 2 4,5-fused phenyl 1179 2,4-F 2 4,5-fusedphenyl 1180 2-CN 2 4,5-fused phenyl 1181 3-CN 2 4,5-fused phenyl 11824-CN 2 4,5-fused phenyl 1183 2-CF₃ 2 4,5-fused phenyl 1184 3-CF₃ 24,5-fused phenyl 1185 4-CF₃ 2 4,5-fused phenyl 1186 H 2 4,5-fused phenyl1187 2-OCH₃ 2 4,5-fused phenyl 1188 3-OCH₃ 2 4,5-fused phenyl 11894-OCH₃ 2 4,5-fused phenyl 1190 2-CH₃ 2 4,5-fused phenyl 1191 3-CH₃ 24,5-fused phenyl 1192 4-CH₃ 2 4,5-fused phenyl

In Examples 1093-1117, R⁵ is taken with ring B when n=2 to form ring Qas follow:

UTILITY

The compounds of this invention are useful as antagonists for thetreatment or prevention of CNS disorders such as anxiety, depression,sleep disorders, and schizophrenia.

SEROTONIN-7 (5-HT₇) BINDING ASSAY

Serotonin-7 (5-HT₇) receptor binding was conducted using the method ofRoth et al (1994). The cloned rat 5-HT₇ was expressed in HEK-293 cells.An aliquot of frozen membranes was thawed and diluted with ice coldbuffer containing 50 mM Tris, 10 mM MgCl₂, and 0.5 mM EDTA (pH 7.4 at22° C.) to approximately 102 μg/ml. Binding of [³H]-LSD to the 5-HT₇receptor was initiated by the addition of 20.4 μg of membranes, 0.5 nM[³H]-LSD, and concentrations of compounds ranging from 1×10⁻⁵ to 1×10⁻¹¹M in total volume of 200 μl. Each concentration was run in duplicate.Nonspecific binding was defined by 100 mM unlabeled 5-HT.

After 60 minutes at 22° C., bound and free ligand were separated byrapid filtration through Packard glass fiber filters (presoaked in 0.2%PEI-polyethyline-amine) on a Tomtec harvester. Filters were air or ovendried and placed in a Packard Topcount for counting.

Inibition of the binding of the radiolabelled ligand was analyzed byusing linear regression analysis of the logit transformation of thepercent bound data. Inhibition constants (K_(i)) are the concentrationof the inhibitors that inhibit binding by 50% divided by the sum of “oneplus the quotient of the radioligand concentration” divided by “theaffinity constant of the radioligand”. The relationship betweeninhibition constant (K_(i)) and the concentration of inhibitor whichcauses 50 percent inhibition (IC₅₀) of an enzymatic reaction may beestablished by methods described by Cheng Y C and Prusoff W H., Biochem.Pharmacol. 1973, 22, 3099-3108, and the binding of typical and atypicalantipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7receptors is described in Roth B L, Craigo S C, Choudhary M S, Uluer A,Monsma F J Jr, Shen Y, Meltzer H Y and Sibley D R. in J. Pharmacol ExpTher. 1994, 268, 1403-1410, the disclosures of which are both herebyincorporated by reference.

DOSAGE AND FORMULATION

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition. Gelatincapsules may contain the active ingredient and powdered carriers, suchas lactose, starch, cellulose derivatives, magnesium stearate, stearicacid, and the like. Similar diluents can be used to make compressedtablets. Both tablets and capsules can be manufactured as sustainedrelease products to provide for continuous release of medication over aperiod of hours. Compressed tablets can be sugar coated or film coatedto mask any unpleasant taste and protect the tablet from the atmosphere,or enteric coated for selective disintegration in the gastrointestinaltract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Representative useful pharmaceutical dosage-formsfor administration of the compounds of this invention can be illustratedas follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed is:
 1. A compound of formula (I):

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein: R¹ is selected from a C₆₋₁₀ carbocyclic aromatic residuesubstituted with 1-3 R^(1a), and a 5-10 membered aromatic heterocyclicsystem containing from 1-4 heteroatoms selected from N, O and S,substituted with 0-2 R^(1a); R^(1a) is independently selected at eachoccurrence from halo, —NO₂, —CN, —CF₃ and —CF₂CF₃; X is selected from—S(O)₂—, —S(O)—, —S—; R⁴ is selected from hydrogen and C₁₋₆ alkyl;R^(4a) is taken together with R¹ to form a 5 or 6-membered fusedheterocyclic ring containing 1-2 heteroatoms selected from O and N,substituted with 1 or 2 carbonyl groups; Y is C₁₋₃ alkylene; A isselected from a 5 or 6 membered saturated, partially saturated orunsaturated ring which contains from 0-1 heteroatoms selected from N, Oand S, substituted with 0-3 R⁵, napthyl substituted with 0-3 R⁵, andnapthyl fused with ring B substituted with 0-3 R⁵; R⁵ is selected fromC₁₋₅ alkyl, halo and —OCH₃; n is selected from 1, 2, and
 3. 2. Thecompound of claim 1, wherein: R¹ is phenyl substituted with 1-3 R^(1a);R^(1a) is selected independently at each occurrence from halo, —CN, —CF₃and —CF₂CF₃; X is selected from —S(O)₂—and —S—; R^(4a) is taken togetherwhen R¹ is phenyl to form a 5 membered fused cyclic urea; Y ispropylene; A is selected from phenyl substituted with 0-3 R⁵, napthylsubstituted with 0-3 R⁵ and napthyl fused with ring B substituted with0-3 R⁵; R⁵ is selected independently at each occurrence from C₁₋₅ alkyl,halo and —OCH₃; and n is selected from 1 and
 2. 3. The compound of claim2, wherein: R¹ is phenyl substituted with 1-3 R^(1a); R^(1a) is selectedindependently at each occurrence from para-halo and meta-fluoro; X isselected from —S(O)₂—, —S— ; Y is propylene; A is phenyl substitutedwith 0-2 R⁵; R⁵ is selected independently at each occurrence from C₁₋₅alkyl, halo and —OCH₃; and n is selected from 1 and
 2. 4. The compoundof claim 3, wherein: R¹ is phenyl substituted with 1-3 R^(1a); R^(1a) ismeta-fluoro; X is selected from —S(O)₂—and —S— ; Y is propylene; A isphenyl substituted with 0-2 R⁵; R⁵ is selected independently at eachoccurrence from C₁₋₅ alkyl, halo and —OCH₃; and n is selected from 1 and2.
 5. A compound of claim 1, selected from:2-((3-(4-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline,1,3-Dihydro-2-((3-(4-fluorophenylthio)propyl))isoindole,1,3-Dihydro-2-((3-(4-fluorophenylsulfonyl)propyl)) isoindole,2-((3-(4-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,2-((3-(3-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline2-((3-(3-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,2-((3-(4-Fluorophenylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,2-((3-(4-Pyridylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,2-((3-(2-Thienylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,2-((3-(3-Thienylsulfonyl)propyl))-1,2,3,4-tetrahydroisoquinoline,1,3-Dihydro-2-((1-(3-thienylsulfonyl)propyl))isoindole,1,3-Dihydro-2-((1-(2-thienylsulfonyl)propyl))isoindole,1,3-Dihydro-2-((1-(4-fluorophenylsulfonyl)propyl)) isoindole,1,3-Dihydro-2-((1-(3-fluorophenylsulfonyl)propyl)) isoindole,1,3-Dihydro-2-((1-(4-pyridylsulfonyl)propyl))isoindole, and1,3-Dihydro-2-((1-(3-pyridylsulfonyl)propyl))isoindole.
 6. Apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 1 or a pharmaceutically acceptable salt thereof.
 7. A methodfor treating or preventing a central nervous system disorder includingsleep disorders, depression and schizophrenia, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof.
 8. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundaccording to claim 2 or a pharmaceutically acceptable salt thereof.
 9. Apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 3 or a pharmaceutically acceptable salt thereof.
 10. Apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 4 or a pharmaceutically acceptable salt thereof.
 11. Apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 5 or a pharmaceutically acceptable salt thereof.
 12. A methodfor treating or preventing a central nervous system disorder includingsleep disorders, depression and schizophrenia, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound according to claim 2 or a pharmaceutically acceptable saltthereof.
 13. A method for treating or preventing a central nervoussystem disorder including sleep disorders, depression and schizophrenia,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound according to claim 3 or apharmaceutically acceptable salt thereof.
 14. A method for treating orpreventing a central nervous system disorder including sleep disorders,depression and schizophrenia, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound accordingto claim 4 or a pharmaceutically acceptable salt thereof.
 15. A methodfor treating or preventing a central nervous system disorder includingsleep disorders, depression and schizophrenia, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound according to claim 5 or a pharmaceutically acceptable saltthereof.